Comparative Tolerability of Dopamine D2/3 Receptor Partial Agonists for Schizophrenia

Abstract

Aripiprazole, brexpiprazole and cariprazine differ from all other second-generation antipsychotics due to partial agonism at the dopamine D2 and D3 receptors. In contrast to aripiprazole, brexpiprazole has lower intrinsic dopamine D2 activity and higher affinity for the serotonin 5-HT1A and 5-HT2A receptors, while cariprazine has the highest affinity for the dopamine D3 receptor, and the longest half-life. The main adverse effect of dopamine receptor partial agonists (DRPAs) is akathisia of low-to-moderate severity, which occurs in a small proportion of patients, usually in the first few weeks of treatment. While definitive conclusions concerning differences between the DRPAs require head-to-head comparison studies, on the available evidence, akathisia is probably least likely to occur with brexpiprazole and most likely with cariprazine; the risk of akathisia with aripiprazole lies in between. Weight-gain risk is low with aripiprazole and cariprazine, but moderate with brexpiprazole. Risk of sedation is low with DRPAs, as is risk of insomnia and nausea. Partial dopamine agonism leads to a low risk for hyperprolactinaemia (and probably a low risk of sexual dysfunction). Prolactin concentrations fall in some patients (particularly those with elevated levels prior to initiating the drugs). Rates of discontinuation due to adverse effects in pivotal studies were low, and on the whole, DRPAs are well tolerated. Aripiprazole has been implicated in pathological gambling and other impulse control behaviours, likely due to partial dopamine agonist activity (there have been no reports with brexpiprazole and cariprazine). The risks for diabetes and tardive dyskinesia with DRPAs are unknown, but are likely to be low. On the basis of tolerability, DRPAs should be considered as first-line treatment options, particularly in patients with early schizophrenia.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2:e141.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet. 2015;386:743–800.

    Article  Google Scholar 

  3. 3.

    Torniainen M, Mittendorfer-Rutz E, Tanskanen A, Bjorkenstam C, Suvisaari J, Alexanderson K, et al. Antipsychotic treatment and mortality in schizophrenia. Schizophr Bull. 2015;41:656–63.

    PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). The Lancet. 2009;374:620–7.

    Article  Google Scholar 

  5. 5.

    Galletly C, Castle D, Dark F, Humberstone V, Jablensky A, Killackey E, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust N Z J Psychiatry. 2016;50:410–72.

    PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Keks NA. Are atypical antipsychotics advantageous? - The case for. Aust Prescr. 2004;27:146–9.

    Article  Google Scholar 

  7. 7.

    Kane J. Clozapine for the treatment-resistant schizophrenic. Arch Gen Psychiatry. 1988;45:789–96.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res. 1999;35:51-68.

  9. 9.

    Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs. 2002;16:77–89.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Koro CE. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study. BMJ. 2002;325:243–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Saha S, Chant D, McGrath J. A systematic review of mortality in Schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64:1123–31.

    PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, 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. The Lancet. 2019;394:939–51.

    CAS  Article  Google Scholar 

  13. 13.

    Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E, et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2003;60:681–90.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Aringhieri S, Carli M, Kolachalam S, Verdesca V, Cini E, Rossi M, et al. Molecular targets of atypical antipsychotics: from mechanism of action to clinical differences. Pharmacol Ther. 2018;192:20–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Tamminga CA. Partial dopamine agonists in the treatment of psychosis. J Neural Trans. 2002;109:411–20.

    CAS  Article  Google Scholar 

  16. 16.

    Carlsson A. Dopamine receptor agonists: intrinsic activity vs. state of receptor. J Neural Trans 1983;57:309–15.

  17. 17.

    Lahti AC, Weiler MA, Corey PK, Lahti RA, Carlsson A, Tamminga CA. Antipsychotic Properties of the partial dopamine agonist (−)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (preclamol) in schizophrenia. Biol Psychiat. 1998;43:2–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, et al. 7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol Exp Ther. 1995;274:329–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Kiss B, Horváth A, Némethy Z, Schmidt É, Laszlovszky I, Bugovics G, et al. Cariprazine (RGH-188), a dopamine D3 receptor-preferring, D3/D2 dopamine receptor antagonist–partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010;333:328–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Otsuka. ABILIFY (Aripiprazole) Tablets, ABILIFY DISCMELT (Aripiprazole) Orally Disintegrating Tablets, ABILIFY (Ariprprazole) Oral Solution, ABILIFY (Aripiprazole) Injection for Intramuscular use Only. Prescribing Information, Revised August 2016. [cited 2019 10th September]; Available from: http://www.otsuka-us.com/Documents/Abilify.PI.pdf

  21. 21.

    Otsuka. REXULTI (Brexpiprazole) tablets, for oral use. Prescribing information, revised February 2018. [cited 2019 10th September]; Available from: http://www.otsuka-us.com/Products/Documents/Rexulti.PI.pdf.

  22. 22.

    Actavis. VRAYLAR (Cariprazine) Capsules, for Oral use. Prescribing information, revised September 2015. [cited; Available from: http://pi.actavis.com/data_stream.asp?product_group=2028&p=pi.

  23. 23.

    Boulay D, Depoortere R, Oblin A, Sanger DJ, Schoemaker H, Perrault G. Haloperidol-induced catalepsy is absent in dopamine D2, but maintained in dopamine D3 receptor knock-out mice. Eur J Pharmacol. 2000;391:63–73.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Kaar SJ, Natesan S, McCutcheon R, Howes OD. Antipsychotics: mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology.https://doi.org/10.1016/j.neuropharm.2019.107704.

  25. 25.

    Horacek J, Bubenikova-Valesova V, Kopecek M, Palenicek T, Dockery C, Mohr P, et al. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs. 2006 2006/05/01;20:389-409.

  26. 26.

    Farde L, Nordström A-L, Wiesel F-A, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992;49:538–44.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Kapur S. Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. 2000;157:514–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Kapur S, Seeman P. Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action. J Psychiatry Neurosci. 2000;25:161–6.

  29. 29.

    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 [11C]-(+)-PHNO. Psychopharmacology. 2016;233:3503–12.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Gründer G, Fellows C, Janouschek H, Veselinovic T, Boy C, Bröcheler A, et al. Brain and plasma pharmacokinetics of aripiprazole in patients with schizophrenia: an [18 F]Fallypride PET study. Am J Psychiatry. 2008;165:988–95.

    PubMed  Article  Google Scholar 

  31. 31.

    Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther. 2002;302:381–9.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Maeda K, Sugino H, Akazawa H, Amada N, Shimada J, Futamura T, et al. Brexpiprazole I: In vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Therap. 2014;350:589–604.

  33. 33.

    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.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Stahl SM. Mechanism of action of cariprazine. CNS Spectr. 2016;21:123–7.

    PubMed  Article  Google Scholar 

  35. 35.

    Citrome L, Stensbøl TB, Maeda K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treatment of psychiatric disorders? Expert Rev Neurother. 2015;15:1219–29.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Aihara K, Shimada J, Miwa T, Tottori K, Burris KD, Yocca FD, et al. The novel antipsychotic aripiprazole is a partial agonist at short and long isoforms of D2 receptors linked to the regulation of adenylyl cyclase activity and prolactin release. Brain Res. 2004;1003:9–17.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Awad AG. Revisiting the concept of subjective tolerability to antipsychotic medications in schizophrenia and its clinical and research implications: 30 years later. CNS Drugs. 2019;33:1–8.

    PubMed  Article  Google Scholar 

  38. 38.

    Mizrahi R, Rusjan P, Agid O, Graff A, Mamo DC, Zipursky RB, et al. Adverse subjective experience with antipsychotics and its relationship to striatal and extrastriatal D2Receptors: a PET study in schizophrenia. Am J Psychiatry. 2007;164:630–7.

    PubMed  Article  Google Scholar 

  39. 39.

    Mizrahi R, Mamo D, Rusjan P, Graff A, Houle S, Kapur S. The relationship between subjective well-being and dopamine D2 receptors in patients treated with a dopamine partial agonist and full antagonist antipsychotics. Int J Neuropsychopharmacol. 2009;12:715.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Inder WJ, Castle D. Antipsychotic-induced hyperprolactinaemia. Aust N Z J Psychiatry. 2011;45:830–7.

    PubMed  Article  Google Scholar 

  41. 41.

    Grimm O, Kaiser S, Plichta MM, Tobler PN. Altered reward anticipation: Potential explanation for weight gain in schizophrenia? Neurosci Biobehav Rev. 2017;75:91–103.

    PubMed  Article  Google Scholar 

  42. 42.

    Sokoloff P, Le Foll B. The dopamine D3 receptor, a quarter century later. Eur J Neurosci. 2016;45:2–19.

    PubMed  Article  Google Scholar 

  43. 43.

    Lahti AC, Weiler M, Carlsson A, Tamminga CA. Effects of the D3 and autoreceptor-preferring dopamine antagonist (+)-UH232 in schizophrenia. J Neural Transmission. 1998;105:719–34.

    CAS  Article  Google Scholar 

  44. 44.

    Lacroix LP, Ceolin L, Zocchi A, Varnier G, Garzotti M, Curcuruto O, et al. Selective dopamine D3 receptor antagonists enhance cortical acetylcholine levels measured with high-performance liquid chromatography/tandem mass spectrometry without anti-cholinesterases. J Neurosci Methods. 2006;157:25–31.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Frank A, Kiss DJ, Keserű GM, Stark H. Binding kinetics of cariprazine and aripiprazole at the dopamine D3 receptor. Sci Rep. 2018;8:12509.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Harvey PD, Koren D, Reichenberg A, Bowie CR. Negative symptoms and cognitive deficits: what is the nature of their relationship? Schizophr Bull. 2006;32:250–8.

    PubMed  Article  Google Scholar 

  47. 47.

    Meltzer HY, Sumiyoshi T. Does stimulation of 5-HT1A receptors improve cognition in schizophrenia? Behav Brain Res. 2008;195:98–102.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Bantick RA, Deakin JFW, Grasby PM. The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics? J Psychopharmacol. 2001;15:37–46.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Blier P, Ward NM. Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiat. 2003;53:193–203.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Frankel JS, Schwartz TL. Brexpiprazole and cariprazine: distinguishing two new atypical antipsychotics from the original dopamine stabilizer aripiprazole. Therap Adv Psychopharmacol. 2017;7:29–41.

    CAS  Article  Google Scholar 

  51. 51.

    Joshi RS, Singh SP, Panicker MM. 5-HT2A deletion protects against Clozapine-induced hyperglycemia. J Pharmacol Sci. 2019;139:133–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu L-X, Sibley DR, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28:1400–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Auclair AL, Cathala A, Sarrazin F, Depoortère R, Piazza PV, Newman-Tancredi A, et al. The central serotonin2B receptor: a new pharmacological target to modulate the mesoaccumbens dopaminergic pathway activity. J Neurochem. 2010;114:1323–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Gunes A, Dahl M-L, Spina E, Scordo MG. Further evidence for the association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients. Eur J Clin Pharmacol. 2008;64:477–82.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Reynolds GP, Zhang Z-J, Zhang X-B. Association of antipsychotic drug induced weight gain with a 5-HT2C receptor gene polymorphism. The Lancet. 2002;359:2086–7.

    CAS  Article  Google Scholar 

  56. 56.

    Lord CC, Wyler SC, Wan R, Castorena CM, Ahmed N, Mathew D, et al. The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C. J Clin Investig. 2017;127:3402–6.

    PubMed  Article  Google Scholar 

  57. 57.

    Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003;28:519–26.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Kanamitsu K, Nozaki Y, Nagaya Y, Sugiyama Y, Kusuhara H. Quantitative prediction of histamine H1 receptor occupancy by the sedative and non-sedative antagonists in the human central nervous system based on systemic exposure and preclinical data. Drug Metab Pharmacokinet. 2017;32:135–44.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics. CNS Drugs. 2007;21:911–36.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Keks N, Schwartz D, Hope J. Stopping and switching antipsychotic drugs. Aust Prescr. 2019;42:152.

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Lohr JB, Eidt CA, Abdulrazzaq Alfaraj A, Soliman MA. The clinical challenges of akathisia. CNS Spectr. 2015;20:1–16.

    PubMed  Article  Google Scholar 

  62. 62.

    Hansen L. A critical review of akathisia, and its possible association with suicidal behaviour. Hum Psychopharmacol Clin Exp. 2001;16:495–505.

    Article  Google Scholar 

  63. 63.

    Drake RE, Ehrlich J. Suicide attempts associated with akathisia. Am J Psychiatry. 1985;142:499–501.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Galynker II, Nazarian D. Akathisia as violence. J Clin Psychiatry. 1997;58:31–2.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Duncan EJ, Adler LA, Stephanides M, Sanfilipo M, Angrist B. Akathisia and exacerbation of psychopathology: a preliminary report. Clin Neuropharmacol. 2000;23:169–73.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2002;63:763–71.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    McEvoy JP, Daniel DG, Carson WH, McQuade RD, Marcus RN. A randomized, double-blind, placebo-controlled, study of the efficacy and safety of aripiprazole 10, 15 or 20mg/day for the treatment of patients with acute exacerbations of schizophrenia. J Psychiatr Res. 2007;41:895–905.

    PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Kasper S, Lerman MN, McQuade RD, Saha A, Carson WH, Ali M, et al. Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol. 2003;6:325–37.

  69. 69.

    Pigott TA, Carson WH, Saha AR, Torbeyns AR, Stock EG, Ingenito GG. Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study. J Clin Psychiatry. 2003;64:1048–56.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Zimbroff D, Warrington L, Loebel A, Yang R, Siu C. Comparison of ziprasidone and aripiprazole in acutely ill patients with schizophrenia or schizoaffective disorder: a randomized, double-blind, 4-week study. Int Clin Psychopharmacol. 2007;22:363–70.

    PubMed  Article  PubMed Central  Google Scholar 

  71. 71.

    Kane J, Osuntokun O, Kryzhanovskaya L, Xu W, Stauffer V, Watson S, et al. A 28-week, randomized, double-blind study of olanzapine versus aripiprazole in the treatment of schizophrenia. J Clin Psychiatry. 2009;70:572–81.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Fleischhacker WW, McQuade RD, Marcus RN, Archibald D, Swanink R, Carson WH. A double-blind, randomized comparative study of aripiprazole and olanzapine in patients with schizophrenia. Biol Psychiat. 2009;65:510–7.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Robinson DG, Gallego JA, John M, Petrides G, Hassoun Y, Zhang J-P, et al. A randomized comparison of aripiprazole and risperidone for the acute treatment of first-episode schizophrenia and related disorders: 3-month outcomes. Schizophr Bull. 2015;41:1227–36.

    PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Findling RL, Robb A, Nyilas M, Forbes RA, Jin N, Ivanova S, et al. A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. Am J Psychiatry. 2008;165:1432–41.

    PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Correll C, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade R, et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind. Placebo-controlled trial. Am J Psychiatry. 2015;172:870–80.

    PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Kane JM, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res. 2015;164:127–35.

    PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Ishigooka J, Iwashita S, Tadori Y. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia in Japan: a 6-week, randomized, double-blind, placebo-controlled study. Psychiatry Clin Neurosci. 2018;72:692–700.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Fleischhacker WW, Hobart M, Ouyang J, Forbes A, Pfister S, McQuade RD, et al. Efficacy and safety of brexpiprazole (OPC-34712) as maintenance treatment in adults with schizophrenia: a randomized, double-blind. Placebo-controlled study. Int J Neuropsychopharmacol. 2017;20:11–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Kane JM, Skuban A, Hobart M, Ouyang J, Weiller E, Weiss C, et al. Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia. Schizophr Res. 2016;174:93–8.

    PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Frampton JE. Brexpiprazole: a review in schizophrenia. Drugs. 2019;79:189–200.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. 81.

    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.

    PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    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.

    PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    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.

    PubMed  Article  PubMed Central  Google Scholar 

  85. 85.

    Lao KSJ, He Y, Wong ICK, Besag FMC, 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.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract. 2013;67:407–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Peña MS, Yaltho TC, Jankovic J. Tardive dyskinesia and other movement disorders secondary to aripiprazole. Mov Disord. 2011;26:147–52.

    PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Solmi M, Murru A, Pacchiarotti I, Undurraga J, Veronese N, Fornaro M, et al. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag. 2017;13:757–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Stegmayer K, Walther S, van Harten P. Tardive dyskinesia associated with atypical antipsychotics: prevalence. Mechanisms and management strategies. CNS Drugs. 2018;32:135–47.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Szatmari B, Barabassy A, Laszlovsky I, Harsanyi J, Acsai K, Burjan A, et al. Safety profile of cariprazine: post hoc analysis of safety parameters of pooled cariprazine schizophrenia studies. 31st Congress of the European College of Neuropsychopharmacology. Barcelona, Spain; 2018. p. 618.

  91. 91.

    Citrome L. Activating and sedating adverse effects of second-generation antipsychotics in the treatment of schizophrenia and major depressive disorder. J Clin Psychopharmacol. 2017;37:138–47.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Dibonaventura M, Gabriel S, Dupclay L, Gupta S, Kim E. A patient perspective of the impact of medication side effects on adherence: results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry. 2012;12:20.

    PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Citrome L, Ota A, Nagamizu K, Perry P, Weiller E, Baker RA. The effect of brexpiprazole (OPC-34712) and aripiprazole in adult patients with acute schizophrenia: results from a randomized, exploratory study. Int Clin Psychopharmacol. 2016;31:192–201.

    PubMed  Article  PubMed Central  Google Scholar 

  94. 94.

    Bak M, Fransen A, Janssen J, Van Os J, Drukker M. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS ONE. 2014;9:e94112.

    PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Álvarez-Jiménez M, Hetrick SE, González-Blanch C, Gleeson JF, McGorry PD. Non-pharmacological management of antipsychotic-induced weight gain: Systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry. 2008;193:101–7.

    PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Allison DB, Mackell JA, McDonnell DD. The impact of weight gain on quality of life among persons with schizophrenia. Psychiatric Services. 2003;54:565–7.

    PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Weiss C, Weiller E, Baker RA, Duffy RA, Gwin KK, Zhang P, et al. The effects of brexpiprazole and aripiprazole on body weight as monotherapy in patients with schizophrenia and as adjunctive treatment in patients with major depressive disorder: an analysis of short-term and long-term studies. Int Clin Psychopharmacol. 2018;33:255–60.

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Lakka H-M. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709.

    PubMed  Article  PubMed Central  Google Scholar 

  99. 99.

    De Hert M, Dekker JM, Wood D, Kahl KG, Holt RIG, Möller HJ. Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). European Psychiatry. 2009;24:412–24.

    PubMed  Article  PubMed Central  Google Scholar 

  100. 100.

    Laursen TM, Munk-Olsen T, Vestergaard M. Life expectancy and cardiovascular mortality in persons with schizophrenia. Curr Opin Psychiatry. 2012;25:83–8.

    PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M, Gebhardt N, Remschmidt H, Krieg J-C, et al. Antipsychotic-induced body weight gain: predictors and a systematic categorization of the long-term weight course. J Psychiatr Res. 2009;43:620–6.

    PubMed  Article  PubMed Central  Google Scholar 

  102. 102.

    Lett TAP, Wallace TJM, Chowdhury NI, Tiwari AK, Kennedy JL, Müller DJ. Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry. 2012;17:242–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, et al. Head-to-head comparisons of metabolic side effects of second-generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2010;123:225–33.

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and management of obesity. N Engl J Med. 2017;376:254–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105.

    Newcomer JW, Eriksson H, Zhang P, Weiller E, Weiss C. Changes in metabolic parameters and body weight in brexpiprazole-treated patients with acute schizophrenia: pooled analyses of phase 3 clinical studies. Curr Med Res Opin. 2018;34:2197–205.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. 106.

    Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7:64–77.

    PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Ward K, Citrome L. Brexpiprazole for the maintenance treatment of adults with schizophrenia: an evidenced-based review and place in therapy. Neuropsychiatr Dis Treat. 2019;15:247–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Garnock-Jones KP. Brexpiprazole: a review in schizophrenia. CNS Drugs. 2016;30:335–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects. CNS Drugs. 2005;19:1–93.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. 110.

    Citrome L, Kalsekar I, Baker RA, Hebden T. A review of real-world data on the effects of aripiprazole on weight and metabolic outcomes in adults. Curr Med Res Opin. 2014;30:1629–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Nielsen J, Skadhede S, Correll CU. Antipsychotics associated with the development of type 2 diabetes in antipsychotic-Naïve schizophrenia patients. Neuropsychopharmacology. 2010;35:1997–2004.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Rubin DM, Kreider AR, Matone M, Huang Y-S, Feudtner C, Ross ME, et al. Risk for incident diabetes mellitus following initiation of second-generation antipsychotics among medicaid-enrolled youths. JAMA Pediatrics. 2015;169:e150285.

    PubMed  Article  Google Scholar 

  113. 113.

    Green AI, Brown WA. Prolactin and neuroleptic drugs. Endocrinol Metab Clin North Am. 1988;17:213–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Keks NA, Copolov DL, Singh BS. Abnormal prolactin response to haloperidol challenge in men with schizophrenia. Am J Psychiatry. 1987;144:1335–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  115. 115.

    Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia. Drugs. 2004;64:2291–314.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    Meaney AM, O’Keane V. Bone mineral density changes over a year in young females with schizophrenia: Relationship to medication and endocrine variables. Schizophr Res. 2007;93:136–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117.

    Bushe C, Shaw M. Prevalence of hyperprolactinaemia in a naturalistic cohort of schizophrenia and bipolar outpatients during treatment with typical and atypical antipsychotics. J Psychopharmacol. 2007;21:768–73.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. 118.

    Ivkovic J, Lindsten A, George V, Eriksson H, Hobart M. Effect of brexpiprazole on prolactin. J Clin Psychopharmacol. 2019;39:13–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    FDA. FDA Drug Safety Communication: FDA warns about new impulse-control problems associated with mental health drug aripiprazole (Abilify, Abilify Maintena, Aristada). 2016 [cited 2019 August 25]; Available from: https://www.fda.gov/Drugs/DrugSafety/ucm498662,htm?source=govdelivery.

  120. 120.

    Etminan M, Sodhi M, Samii A, Procyshyn RM, Guo M, Carleton BC. Risk of gambling disorder and impulse control disorder with aripiprazole, pramipexole, and ropinirole: a pharmacoepidemiologic study. J Clin Psychopharmacol. 2017;37:102–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. 121.

    Lachance A, Corbeil O, Corbeil S, Chalifour G, Breault A-S, Roy M-A, et al. Case reports of aripiprazole and problematic gambling in schizophrenia: a critical review of the evidence. J Clin Psychopharmacol. 2019;39:393–7.

    PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Murri B, Guaglianone A, Bugliani M, Calcagno P, Respino M, Serafini G, et al. Second-generation antipsychotics and neuroleptic malignant syndrome: systematic review and case report analysis. Drugs R&D. 2015;15:45–62.

    Article  CAS  Google Scholar 

  123. 123.

    Bortolato B, Miskowiak K, Köhler C, Vieta E, Carvalho AF. Cognitive dysfunction in bipolar disorder and schizophrenia: a systematic review of meta-analyses. Neuropsychiatr Dis Treat. 2015;11:3111–25.

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Sakurai H, Bies RR, Stroup ST, Keefe RSE, Rajji TK, Suzuki T, et al. Dopamine D2 receptor occupancy and cognition in schizophrenia: analysis of the CATIE data. Schizophr Bull. 2013;39:564–74.

    PubMed  Article  PubMed Central  Google Scholar 

  125. 125.

    Kern RS, Green MF, Cornblatt BA, Owen JR, McQuade RD, Carson WH, et al. The neurocognitive effects of aripiprazole: an open-label comparison with olanzapine. Psychopharmacology. 2006;187:312–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  126. 126.

    Gugger JJ. Antipsychotic pharmacotherapy and orthostatic hypotension. CNS Drugs. 2011;25:659–71.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. 127.

    Yood MU, Delorenze G, Quesenberry CP, Tsai A-L, Phillips S, Willey VJ, et al. Epidemiologic study of aripiprazole use and the incidence of suicide events. Pharmacoepidemiol Drug Saf. 2010;19:1124–30.

    Article  Google Scholar 

  128. 128.

    Croxtall JD. Aripiprazole. CNS Drugs. 2012;26:155–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. 129.

    Takase M, Kanahara N, Oda Y, Kimura H, Watanabe H, Iyo M. Dopamine supersensitivity psychosis and dopamine partial agonist: a retrospective survey of failure of switching to aripiprazole in schizophrenia. Journal of Psychopharmacology. 2015;29:383–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. 130.

    Montastruc F, Nie R, Loo S, Rej S, Dell’Aniello S, Micallef J, et al. Association of aripiprazole with the risk for psychiatric hospitalization, self-harm, or suicide. JAMA Psychiatry. 2019;76:409–17.

    PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  132. 132.

    Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet. 2013;382:951–62.

    CAS  Article  Google Scholar 

  133. 133.

    Thase M, Youakim J, Skuban A, Hobart M, Augustine C, Zhang P, et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomised, placebo controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry. 2015;76:1224–31.

    PubMed  Article  PubMed Central  Google Scholar 

  134. 134.

    De Hert M, Detraux J, Peuskens J. Second-generation and newly approved antipsychotics, serum prolactin levels and sexual dysfunctions: a critical literature review. Expert Opin Drug Safety. 2014;13:605–24.

    Article  CAS  Google Scholar 

  135. 135.

    Serretti A, Chiesa A. A meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics. Int Clin Psychopharmacol. 2011;26:130–40.

    PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Kikuchi T, Iwamoto K, Sasada K, Aleksic B, Yoshida K, Ozaki N. Sexual dysfunction and hyperprolactinemia in Japanese schizophrenic patients taking antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37:26–32.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. 137.

    Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: meta-analysis of randomized controlled trials. PLoS One. 2013;8:e70179.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Rahman T, Clevenger C, Kaklamani V, Lauriello J, Campbell A, Malwitz K, et al. Antipsychotic treatment in breast cancer patients. Am J Psychiatry. 2014;171:616–21.

    PubMed  Article  Google Scholar 

  139. 139.

    Sachdev P. Early extrapyramidal side-effects as risk factors for later tardive dyskinesia: a prospective study. Aust N Z J Psychiatry. 2004;38:445–9.

    PubMed  Article  PubMed Central  Google Scholar 

  140. 140.

    Tenback D, van Harten P, Cees S, van Os J. Evidence that early extrapyramidal symptoms predict later tardive dyskinesia: a prospective analysis of 10,000 patients in the European Schizophrenia Outpatient Health Outcomes (SOHO) Study. Am J Psychiatry. 2006;163:1438–40.

    PubMed  Article  Google Scholar 

  141. 141.

    Solmi M, Pigato G, Kane JM, Correll CU. Clinical risk factors for the development of tardive dyskinesia. J Neurol Sci. 2018;389:21–7.

    PubMed  Article  Google Scholar 

  142. 142.

    Keks NA, Hope J. Long term management of people with psychotic disorders in the community. Aust Prescr. 2007;30:44–6.

    Article  Google Scholar 

  143. 143.

    Hargraves I, LeBlanc A, Shah N, Montori V. Shared decision making: the need for patient-clinician conversation, not just information. Health Affairs. 2016;35:627–9.

    PubMed  Article  Google Scholar 

  144. 144.

    Nakamura T, Kubota T, Iwakaji A, Imada M, Kapás M, Morio Y. Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment). Drug Des Devel Ther. 2016;10:327–38.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge Sue Keks for assistance with the editing of this manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Nicholas Keks.

Ethics declarations

Funding

The preparation of this review was supported by research funding to NK and JH from the Pratt Foundation. There were no other sources of support.

Conflict of Interest

NK, JH, HM, DC and GM declare no relevant conflict of interest. DS has received an honorarium from Lundbeck.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Keks, N., Hope, J., Schwartz, D. et al. Comparative Tolerability of Dopamine D2/3 Receptor Partial Agonists for Schizophrenia. CNS Drugs 34, 473–507 (2020). https://doi.org/10.1007/s40263-020-00718-4

Download citation