Symptomatic Profile of Cariprazine in the Context of ICD-11 Domains for Schizophrenia: Review of Clinically Oriented Studies

Abstract

INTRODUCTION: One of the innovations in the ICD-11grouping "Schizophrenia and Other Primary Psychotic Disorders" is the implementation of six symptom domains intended to improve diagnostics and treatment of these mental conditions in clinical practice. In this respect, evaluation of the effects of various psychotropic drugs, primarily antipsychotic agents, on the specified psychotic symptom domains is a critical task. The antipsychotic agent cariprazine, registered in many countries worldwide (including Russia) for schizophrenia treatment, was selected as the psychotropic drug model for the purposes of the present review.

METHODS: For the purposes of this review the MEDLINE, Cochrane Central Register of Controlled Trials, and PubMed databases were searched for randomized controlled trials comparing cariprazine with a placebo, or a placebo and one or several antipsychotic agents, and that was performed within the period from January 2014 to March 2021.

RESULTS: Cariprazine has proved its efficiency in relation to all symptom groups of the ICD-11 domain "Positive Symptoms'', and may be considered a front-line therapy for treatment of the first and multiple episodes of schizophrenia, disorganized thinking, and behavioral disorders in the form of aggressiveness and hostility. Cariprazine has the best evidential base for treatment of various symptoms within the ICD-11 domain "Negative Symptoms'' among all antipsychotic agents. The data with regard to the effects of cariprazine on the domain "Depressive Mood Symptoms'' are controversial. No data concerning the effects of cariprazine on the domain "Maniс Mood Symptoms'' are available, but the effectiveness of cariprazine monotherapy for manic episodes without any psychomotor agitation signs in the instance of bipolar disorder has been demonstrated. The effectiveness of cariprazine therapy for the ICD-11 domain "Psychomotor Symptoms" has not been investigated, either within the framework of monotherapy or in the course of adjuvant therapy. The effectiveness of cariprazine has been demonstrated in treatment of the domain "Cognitive Symptoms", and the pro-cognitive effect of the drug has developed regardless of its impact on any other schizophrenia symptoms. The drug’s capability to improve the functioning of patients with schizophrenia was demonstrated regardless of the impact on psychotic symptoms.

CONCLUSION: Cariprazine is the first-line drug for treatment of the domain "Negative Symptoms" as well as representing front-line therapy for the treatment of ICD-11 domains "Positive Symptoms" and "Cognitive Symptoms". Additional studies will be required in order to evaluate the effects of cariprazine on the ICD-11 domains "Maniс Mood Symptoms" and "Depressive Mood Symptoms".

Keywords

cariprazine / schizophrenia / ICD-11 / symptom domains / PANSS

References

[1] Jablensky A. Towards ICD-11 and DSM-V: issues beyond 'harmonisation'. Br J Psychiatry 2009 Nov;195(5):379–381. doi: 10.1192/bjp.bp.109.071241.

[2] Potuzak M, Ravichandran C, Lewandowski KE, Ongur D, Cohen BM. Categorical vs dimensional classifications of psychotic disorders. Compr Psychiatry 2012 Nov;53(8):1118–1129. doi: 10.1016/j.comppsych.2012.04.010.

[3] Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13(2):261–276. doi: 10.1093/schbul/13.2.261.

[4] Kay SR, Sevy S. Pyramidical model of schizophrenia. Schizophr Bull 1990;16(3):537–545. doi: 10.1093/schbul/16.3.537.

[5] Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997 Dec;58(12):538–546. doi: 10.4088/jcp.v58n1205.

[6] van der Gaag M, Cuijpers A, Hoffman T, et al. The five-factor model of the Positive and Negative Syndrome Scale I: confirmatory factor analysis fails to confirm 25 published five-factor solutions. Schizophr Res 2006 Jul;85(1–3):273–279. doi: 10.1016/j.schres.2006.04.001.

[7] WHO [Internet]. ICD-11 for Mortality and Morbidity Statistics, Chapter 06 [cited 25 Jan 2022]. Available from: https://icd.who.int/browse11/l-m/en

[8] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association; 2013. doi: 10.1176/appi.books.9780890425596.

[9] Gaebel W. Status of psychotic disorders in ICD-11. Schizophr Bull 2012 Sep;38(5):895–898. doi: 10.1093/schbul/sbs104.

[10] Kulygina MA, Syunyakov TS, Fedotov IA, Kostyuk GP. Toward ICD-11 Implementation: Attitudes and Expectations of the Russian Psychiatric Community. Consortium Psychiatricum 2021;2(2):23–34. doi: 10.17816/cp80.

[11] Stahl SM, Laredo S, Morrissette DA. Cariprazine as a treatment across the bipolar I spectrum from depression to mania: mechanism of action and review of clinical data. Ther Adv Psychopharmacol 2020;10:2045125320905752. doi: 10.1177/2045125320905752.

[12] Stahl SM. Mechanism of action of cariprazine. CNS Spectr 2016 Apr;21(2):123–127. doi: 10.1017/S1092852916000043.

[13] Corponi F, Fabbri C, Bitter I, et al. Novel antipsychotics specificity profile: A clinically oriented review of lurasidone, brexpiprazole, cariprazine and lumateperone. Eur Neuropsychopharmacol 2019 Sep;29(9):971–985. doi: 10.1016/j.euroneuro.2019.06.008.

[14] Gross G, Wicke K, Drescher KU. Dopamine D(3) receptor antagonism--still a therapeutic option for the treatment of schizophrenia. Naunyn Schmiedebergs Arch Pharmacol 2013 Feb;386(2):155–166. doi: 10.1007/s00210-012-0806-3.

[15] Zimnisky R, Chang G, Gyertyan I, et al. Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. Psychopharmacology (Berl) 2013 Mar;226(1):91–100. doi: 10.1007/s00213-012-2896-5.

[16] Duric V, Banasr M, Franklin T, et al. Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model. Int J Neuropsychopharmacol 2017 Oct 1;20(10):788–796. doi: 10.1093/ijnp/pyx038.

[17] Misiak B, Bienkowski P, Samochowiec J. Cariprazine — a novel antipsychotic drug and its place in the treatment of schizophrenia. Psychiatr Pol 2018 Dec 29;52(6):971–981. doi: 10.12740/PP/OnlineFirst/80710.

[18] Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol 2013 Feb;9(2):193–206. doi: 10.1517/17425255.2013.759211.

[19] Durgam S, Starace A, Li D, 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 Feb;152(2–3):450–457. doi: 10.1016/j.schres.2013.11.041.

[20] Durgam S, Cutler AJ, Lu K, 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 Dec;76(12):e1574–1582. doi: 10.4088/JCP.15m09997.

[21] Kane JM, Zukin S, Wang Y, et al. Efficacy and Safety of Cariprazine in Acute Exacerbation of Schizophrenia: Results From an International, Phase III Clinical Trial. J Clin Psychopharmacol 2015 Aug;35(4):367–373. doi: 10.1097/JCP.0000000000000346.

[22] Marder S, Fleischhacker WW, Earley W, et al. Efficacy of cariprazine across symptom domains in patients with acute exacerbation of schizophrenia: Pooled analyses from 3 phase II/III studies. Eur Neuropsychopharmacol 2019 Jan;29(1):127–136. doi: 10.1016/j.euroneuro.2018.10.008.

[23] Citrome L, Durgam S, Lu K, Ferguson P, Laszlovszky I. The effect of cariprazine on hostility associated with schizophrenia: post hoc analyses from 3 randomized controlled trials. J Clin Psychiatry 2016 Jan;77(1):109–115. doi: 10.4088/JCP.15m10192.

[24] Durgam S, Earley W, Li R, 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 Oct;176(2–3):264–271. doi: 10.1016/j.schres.2016.06.030.

[25] Correll CU, Potkin SG, Zhong Y, et al. Long-Term Remission With Cariprazine Treatment in Patients With Schizophrenia: A Post Hoc Analysis of a Randomized, Double-Blind, Placebo-Controlled, Relapse Prevention Trial. J Clin Psychiatry 2019 Jan 8;80(2) doi: 10.4088/JCP.18m12495.

[26] Rancans E, Dombi ZB, Matrai P, et al. The effectiveness and safety of cariprazine in schizophrenia patients with negative symptoms and insufficient effectiveness of previous antipsychotic therapy: an observational study. Int Clin Psychopharmacol 2021 May 1;36(3):154–161. doi: 10.1097/YIC.0000000000000351.

[27] Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 2019 Sep 14;394(10202):939–951. doi: 10.1016/S0140-6736(19)31135-3.

[28] Fagiolini A, Alcala JA, Aubel T, et al. Treating schizophrenia with cariprazine: from clinical research to clinical practice. Real world experiences and recommendations from an International Panel. Ann Gen Psychiatry 2020;19:55. doi: 10.1186/s12991-020-00305-3.

[29] Galderisi S, Mucci A, Buchanan RW, Arango C. Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry 2018 Aug;5(8):664–677. doi: 10.1016/S2215-0366(18)30050-6.

[30] Corponi F, Serretti A, Montgomery S, Fabbri C. Cariprazine specificity profile in the treatment of acute schizophrenia: a meta-analysis and meta-regression of randomized-controlled trials. Int Clin Psychopharmacol 2017 Nov;32(6):309–318. doi: 10.1097/YIC.0000000000000189.

[31] Nemeth G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 2017 Mar 18;389(10074):1103–1113. doi: 10.1016/S0140-6736(17)30060-0.

[32] Fleischhacker W, Galderisi S, Laszlovszky I, et al. The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors. Eur Psychiatry 2019 May;58:1–9. doi: 10.1016/j.eurpsy.2019.01.015.

[33] Earley W, Guo H, Daniel D, et al. Efficacy of cariprazine on negative symptoms in patients with acute schizophrenia: A post hoc analysis of pooled data. Schizophr Res 2019 Feb;204:282–288. doi: 10.1016/j.schres.2018.08.020.

[34] Durgam S, Greenberg WM, Li D, et al. Safety and tolerability of cariprazine in the long-term treatment of schizophrenia: results from a 48-week, single-arm, open-label extension study. Psychopharmacology (Berl) 2017 Jan;234(2):199–209. doi: 10.1007/s00213-016-4450-3.

[35] Nasrallah HA, Earley W, Cutler AJ, et al. The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis. BMC Psychiatry 2017 Aug 24;17(1):305. doi: 10.1186/s12888-017-1459-z.

[36] Cerveri G, Gesi C, Mencacci C. Pharmacological treatment of negative symptoms in schizophrenia: update and proposal of a clinical algorithm. Neuropsychiatr Dis Treat 2019;15:1525–1535. doi: 10.2147/NDT.S201726.

[37] Krause M, Zhu Y, Huhn M, et al. Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci 2018 Oct;268(7):625–639. doi: 10.1007/s00406-018-0869-3.

[38] Rossiyskoe obshestvo psikhiatrov [Internet]. Proekt klinicheskikh recomendatsiy “Schizophrenia” (F20) [cited 25 Jan 2022]. Available from: https://psychiatr.ru/download/4244?view=1&name=КР_+Шизофрения+25-11.pdf

[39] Krynicki CR, Upthegrove R, Deakin JFW, Barnes TRE. The relationship between negative symptoms and depression in schizophrenia: a systematic review. Acta Psychiatr Scand 2018 May;137(5):380–390. doi: 10.1111/acps.12873.

[40] Laszlovszky I, Barabassy A, Nemeth G. Cariprazine, A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety. Adv Ther 2021 Jul;38(7):3652–3673. doi: 10.1007/s12325-021-01797-5.

[41] Addington D, Addington J, Maticka-Tyndale E. Assessing depression in schizophrenia: the Calgary Depression Scale. Br J Psychiatry Suppl 1993 Dec;(22):39–44.

[42] Plana-Ripoll O, Pedersen CB, Holtz Y, et al. Exploring Comorbidity Within Mental Disorders Among a Danish National Population. JAMA Psychiatry 2019;76(3):259. doi: 10.1001/jamapsychiatry.2018.3658.

[43] Durgam S, Earley W, Lipschitz A, et al. An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression. Am J Psychiatry 2016 Mar 1;173(3):271–281. doi: 10.1176/appi.ajp.2015.15020164.

[44] Earley WR, Burgess MV, Khan B, et al. Efficacy and safety of cariprazine in bipolar I depression: A double-blind, placebo-controlled phase 3 study. Bipolar Disord 2020 Jun;22(4):372–384. doi: 10.1111/bdi.12852.

[45] Earley W, Burgess MV, Rekeda L, et al. Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study. Am J Psychiatry 2019 Jun 1;176(6):439–448. doi: 10.1176/appi.ajp.2018.18070824.

[46] Yatham LN, Vieta E, McIntyre RS, et al. Broad Efficacy of Cariprazine on Depressive Symptoms in Bipolar Disorder and the Clinical Implications. Prim Care Companion CNS Disord 2020 Sep 17;22(5)doi: 10.4088/PCC.20m02611.

[47] Earley WR, Burgess M, Rekeda L, et al. A pooled post hoc analysis evaluating the safety and tolerability of cariprazine in bipolar depression. J Affect Disord 2020 Feb 15;263:386–395. doi: 10.1016/j.jad.2019.11.098.

[48] Allergan [Internet]. Allergan and Gedeon Richter Receive U.S. FDA Approval For Expanded Use of VRAYLAR® (cariprazine) in the Treatment of Bipolar Depression (news release). Dublin and Budapest. May 28, 2019 [cited 25 Jan 2022]. Available from: https://www.prnewswire.com/news-releases/allergan-and-gedeon-richter-receive-us-fda-approval-for-expanded-use-of-vraylar-cariprazine-in-the-treatment-of-bipolar-depression-300857106.html

[49] Rosminzdrav.ru [Internet]. Instruktsiya po medicinskomu primeneniyu preparata Reagil®: LP- 005405 ot 02.06.2021 [cited 25 Jan 2022]. Available from: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=de967c9d-139a-437b-8b45-937d84e907a4&t=&bx_sender_conversion_id=134165&utm_source=newsletter&utm_medium=mail&utm_campaign=novye_vozmozhnosti_lecheniya_rasstroystv_bipolyarnogo_spektra

[50] Yatham LN, Vieta E, McIntyre RS, et al. Broad Efficacy of Cariprazine on Depressive Symptoms in Bipolar Disorder and the Clinical Implications. Prim Care Companion CNS Disord 2020 Sep 17;22(5)doi: 10.4088/PCC.20m02611.

[51] Fava M, Durgam S, Earley W, et al. Efficacy of adjunctive low-dose cariprazine in major depressive disorder: a randomized, double-blind, placebo-controlled trial. Int Clin Psychopharmacol 2018 Nov;33(6):312–321. doi: 10.1097/YIC.0000000000000235.

[52] German Association for Psychiatry, Psychotherapy and Psychosomatics, DGPPN [Internet]. S3 Guideline for Schizophrenia [cited 25 Jan 2022]. Available from: https://www.dgppn.de/_Resources/Persistent/b794e84f9cbdf0d761b26cb1bd323b65188cb9e6/038-009e_S3_Schizophrenie_2019-03.pdf

[53] Calabrese JR, Keck PE, Jr., Starace A, 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 Mar;76(3):284–292. doi: 10.4088/JCP.14m09081.

[54] Durgam S, Starace A, Li D, et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial. Bipolar Disord 2015 Feb;17(1):63–75. doi: 10.1111/bdi.12238.

[55] Sachs GS, Greenberg WM, Starace A, 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 Mar 15;174:296–302. doi: 10.1016/j.jad.2014.11.018.

[56] Vieta E, Durgam S, Lu K, et al. Effect of cariprazine across the symptoms of mania in bipolar I disorder: Analyses of pooled data from phase II/III trials. Eur Neuropsychopharmacol 2015 Nov;25(11):1882–1891. doi: 10.1016/j.euroneuro.2015.08.020.

[57] Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016 Jun;30(6):495–553. doi: 10.1177/0269881116636545.

[58] Leroy A, Naudet F, Vaiva G, et al. Is electroconvulsive therapy an evidence-based treatment for catatonia? A systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci 2018 Oct;268(7):675–687. doi: 10.1007/s00406-017-0819-5.

[59] Wilson JE, Niu K, Nicolson SE, Levine SZ, Heckers S. The diagnostic criteria and structure of catatonia. Schizophr Res 2015 May;164(1–3):256–262. doi: 10.1016/j.schres.2014.12.036.

[60] Cutler AJ, Durgam S, Wang Y, et al. Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1-year open-label study. CNS Spectr 2018 Feb;23(1):39–50. doi: 10.1017/S1092852917000220.

[61] Gkintoni E, Pallis EG, Bitsios P, Giakoumaki SG. Neurocognitive performance, psychopathology and social functioning in individuals at high risk for schizophrenia or psychotic bipolar disorder. J Affect Disord 2017 Jan 15;208:512–520. doi: 10.1016/j.jad.2016.10.032.

[62] Kuswanto C, Chin R, Sum MY, et al. Shared and divergent neurocognitive impairments in adult patients with schizophrenia and bipolar disorder: Whither the evidence? Neurosci Biobehav Rev 2016 Feb;61:66–89. doi: 10.1016/j.neubiorev.2015.12.002.

[63] Fountoulakis KN, Dragioti E, Theofilidis AT, et al. Staging of Schizophrenia With the Use of PANSS: An International Multi-Center Study. Int J Neuropsychopharmacol 2019 Nov 1;22(11):681–697. doi: 10.1093/ijnp/pyz053.

[64] Neill JC, Grayson B, Kiss B, et al. Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology. Eur Neuropsychopharmacol 2016 Jan;26(1):3–14. doi: 10.1016/j.euroneuro.2015.11.016.

[65] Meltzer HY, Cucchiaro J, Silva R, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry 2011 Sep;168(9):957–967. doi: 10.1176/appi.ajp.2011.10060907.

[66] Galderisi S, Rossi A, Rocca P, et al. The influence of illness-related variables, personal resources and context-related factors on real-life functioning of people with schizophrenia. World Psychiatry 2014 Oct;13(3):275–287. doi: 10.1002/wps.20167.

[67] Laszlovszky I, Acsai K, Barabássy Á, et al. Long-term functional improving effects of cariprazine: post-hoc analyses of acute and predominant negative symptom schizophrenia patient data. European Neuropsychopharmacology. 2020:326–S327. doi: 10.1016/j.euroneuro. 2020.09.421.

[68] Purnine DM, Carey KB, Maisto SA, Carey MP. Assessing positive and negative symptoms in outpatients with schizophrenia and mood disorders. J Nerv Ment Dis 2000 Oct;188(10):653–661. doi: 10.1097/00005053-200010000-00003.

[69] Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand 2000 Apr;101(4):323–329.

[70] Brain C, Allerby K, Sameby B, et al. Drug attitude and other predictors of medication adherence in schizophrenia: 12 months of electronic monitoring (MEMS((R))) in the Swedish COAST-study. Eur Neuropsychopharmacol 2013 Dec;23(12):1754–1762. doi: 10.1016/j.euroneuro.2013.09.001.

[71] Kirkpatrick B, Strauss GP, Nguyen L, et al. The brief negative symptom scale: psychometric properties. Schizophr Bull 2011 Mar;37(2):300–305. doi: 10.1093/schbul/sbq059.

[72] Keefe RS, Harvey PD, Goldberg TE, et al. Norms and standardization of the Brief Assessment of Cognition in Schizophrenia (BACS). Schizophr Res 2008 Jul;102(1–3):108–115. doi: 10.1016/j.schres.2008.03.024.

Funding

Gedeon Richter Russia

RIGHTS & PERMISSIONS

Pavlichenko A.V., Gubina A.S.