Advertisement

Antipsychotics: Overview

  • Oliver Freudenreich
Chapter
Part of the Current Clinical Psychiatry book series (CCPSY)

Abstract

Antipsychotics are effective for the positive symptoms of schizophrenia, both for acute psychosis and for the prevention of relapse. This chapter provides an overview of currently available first-, second-, and third-generation antipsychotics (partial agonists). Their shared mechanism of action (dopamine blockade) but also differences in their complex receptor profiles is used to explain clinical differences between individual antipsychotics, particularly with regard to side effects and optimal dosing. Understanding the historical ideas behind an antipsychotic’s “atypicality” (good efficacy without extrapyramidal side effect) is necessary to understand how newer antipsychotics compare to the older, first-generation antipsychotics. The chapter ends with a discussion of neurotoxicity from antipsychotics and the need for safer and more effective antipsychotics.

Keywords

Antipsychotics Dopamine-2 receptor Mechanism of action First-generation antipsychotics Second-generation antipsychotics Third-generation antipsychotics Neurotoxicity Neuroprotection 

References

  1. 1.
    Wikiquote. William Osler. Available from: https://en.wikiquote.org/wiki/William_Osler. Accessed on 7/1/2019.
  2. 2.
    Sahli ZT, Tarazi FI. Pimavanserin: novel pharmacotherapy for Parkinson’s disease psychosis. Expert Opin Drug Discov. 2018;13:103–10.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Nasrallah HA, Fedora R, Morton R. Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist. Schizophr Res. 2019;208:217–20.CrossRefGoogle Scholar
  4. 4.
    Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophr Bull. 2009;35:549–62.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry. 2003;160:13–23.CrossRefGoogle Scholar
  6. 6.
    Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet. 2012;379:2063–71.CrossRefGoogle Scholar
  7. 7.
    El-Mallakh RS. Receptor occupancy and drug response: understanding the relationship. Curr Psychiatr Ther. 2018;17:8–13.Google Scholar
  8. 8.
    Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry. 2001;158:360–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–96.CrossRefGoogle Scholar
  10. 10.
    Kendall T. The rise and fall of the atypical antipsychotics. Br J Psychiatry. 2011;199:266–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Fischer-Barnicol D, Lanquillon S, Haen E, Zofel P, Koch HJ, Dose M, et al. Typical and atypical antipsychotics--the misleading dichotomy. Results from the Working Group “Drugs in Psychiatry” (AGATE). Neuropsychobiology. 2008;57:80–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Zohar J, Kasper S. Neuroscience-based nomenclature (NbN): a call for action. World J Biol Psychiatry. 2016;17:318–20.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Meltzer HY. What’s atypical about atypical antipsychotic drugs? Curr Opin Pharmacol. 2004;4:53–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Kusumi I, Boku S, Takahashi Y. Psychopharmacology of atypical antipsychotic drugs: from the receptor binding profile to neuroprotection and neurogenesis. Psychiatry Clin Neurosci. 2015;69:243–58.PubMedCrossRefGoogle Scholar
  15. 15.
    Hyman SE, Nestler EJ. Initiation and adaptation: a paradigm for understanding psychotropic drug action. Am J Psychiatry. 1996;153:151–62.PubMedCrossRefGoogle Scholar
  16. 16.
    Glazer WM. Does loxapine have “atypical” properties? Clinical evidence. J Clin Psychiatry. 1999;60(Suppl 10):42–6.PubMedGoogle Scholar
  17. 17.
    Farde L, Wiesel FA, Halldin C, Sedvall G. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry. 1988;45:71–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Nord M, Farde L. Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neurosci Ther. 2011;17:97–103.PubMedCrossRefGoogle Scholar
  19. 19.
    Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36:71–93.CrossRefGoogle Scholar
  20. 20.
    Gardner DM, Murphy AL, O’Donnell H, Centorrino F, Baldessarini RJ. International consensus study of antipsychotic dosing. Am J Psychiatry. 2010;167:686–93.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    McEvoy JP, Hogarty GE, Steingard S. Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry. 1991;48:739–45.CrossRefGoogle Scholar
  22. 22.
    Fang J, McKay G, Song J, Remillrd A, Li X, Midha K. In vitro characterization of the metabolism of haloperidol using recombinant cytochrome p450 enzymes and human liver microsomes. Drug Metab Dispos. 2001;29:1638–43.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Leucht S, Samara M, Heres S, Patel MX, Furukawa T, Cipriani A, et al. Dose equivalents for second-generation antipsychotic drugs: the classical mean dose method. Schizophr Bull. 2015;41:1397–402.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Woods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry. 2003;64:663–7.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    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.CrossRefGoogle Scholar
  26. 26.
    Honer WG, MacEwan GW, Gendron A, Stip E, Labelle A, Williams R, et al. A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2012;73:13–20.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Lindenmayer JP, Citrome L, Khan A, Kaushik S. A randomized, double-blind, parallel-group, fixed-dose, clinical trial of quetiapine at 600 versus 1200 mg/d for patients with treatment-resistant schizophrenia or schizoaffective disorder. J Clin Psychopharmacol. 2011;31:160–8.CrossRefGoogle Scholar
  28. 28.
    Goff DC, McEvoy JP, Citrome L, Mech AW, Bustillo JR, Gil R, et al. High-dose oral ziprasidone versus conventional dosing in schizophrenia patients with residual symptoms: the ZEBRAS study. J Clin Psychopharmacol. 2013;33:485–90.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Meltzer HY. Serotonergic mechanisms as targets for existing and novel antipsychotics. Handb Exp Pharmacol. 2012:87–124.Google Scholar
  30. 30.
    Li C, Xia J, Wang J. Risperidone dose for schizophrenia. Cochrane Database Syst Rev. 2009:CD007474.Google Scholar
  31. 31.
    Volavka J, Czobor P, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry. 2002;159:255–62.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Gandelman K, Alderman JA, Glue P, Lombardo I, LaBadie RR, Versavel M, et al. The impact of calories and fat content of meals on oral ziprasidone absorption: a randomized, open-label, crossover trial. J Clin Psychiatry. 2009;70:58–62.PubMedCrossRefGoogle Scholar
  33. 33.
    Citrome L. Lurasidone for the acute treatment of adults with schizophrenia: what is the number needed to treat, number needed to harm, and likelihood to be helped or harmed? Clin Schizophr Relat Psychoses. 2012;6:76–85.PubMedCrossRefGoogle Scholar
  34. 34.
    Preskorn S, Ereshefsky L, Chiu YY, Poola N, Loebel A. Effect of food on the pharmacokinetics of lurasidone: results of two randomized, open-label, crossover studies. Hum Psychopharmacol. 2013;28:495–505.PubMedCrossRefGoogle Scholar
  35. 35.
    Citrome L, Meng X, Hochfeld M, Stahl SM. Efficacy of iloperidone in the short-term treatment of schizophrenia: a post hoc analysis of pooled patient data from four phase III, placebo- and active-controlled trials. Hum Psychopharmacol. 2012;27:24–32.PubMedCrossRefGoogle Scholar
  36. 36.
    Subeesh V, Maheswari E, Singh H, Beulah TE, Swaroop AM. Novel adverse events of iloperidone: a disproportionality analysis in US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Curr Drug Saf. 2019;14:21–6.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Citrome L. Role of sublingual asenapine in treatment of schizophrenia. Neuropsychiatr Dis Treat. 2011;7:325–39.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Citrome L. Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic. Int J Clin Pract. 2009;63:1762–84.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Goff DC. Brexpiprazole: a new antipsychotic following in the footsteps of aripiprazole. Am J Psychiatry. 2015;172:820–1.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    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.PubMedCrossRefGoogle Scholar
  41. 41.
    Stroup TS, McEvoy JP, Ring KD, Hamer RH, LaVange LM, Swartz MS, et al. A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP). Am J Psychiatry. 2011;168:947–56.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Moreira FA, Dalley JW. Dopamine receptor partial agonists and addiction. Eur J Pharmacol. 2015;752:112–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Moore TJ, Glenmullen J, Mattison DR. Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs. JAMA Intern Med. 2014;174:1930–3.PubMedCrossRefGoogle Scholar
  44. 44.
    Giri YR, Peteru SR. Escalation of gambling associated with aripiprazole: a case report and literature review. J Psychiatr Pract. 2019;25:139–45.PubMedCrossRefGoogle Scholar
  45. 45.
    Calabrese F, Tarazi FI, Racagni G, Riva MA. The role of dopamine D3 receptors in the mechanism of action of cariprazine. CNS Spectr. 2019:1–9.Google Scholar
  46. 46.
    Citrome L. Brexpiprazole: a new dopamine D(2)receptor partial agonist for the treatment of schizophrenia and major depressive disorder. Drugs Today. 2015;51:397–414.PubMedCrossRefGoogle Scholar
  47. 47.
    Nakamura T, Kubota T, Iwakaji A, Imada M, Kapas 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.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Nemeth G, Laszlovszky I, Czobor P, Szalai E, Szatmari B, Harsanyi J, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017;389:1103–13.PubMedCrossRefGoogle Scholar
  49. 49.
    Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383:533–40.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA. The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychopharmacology. 2005;30:1649–61.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Lesh TA, Tanase C, Geib BR, Niendam TA, Yoon JH, Minzenberg MJ, et al. A multimodal analysis of antipsychotic effects on brain structure and function in first-episode schizophrenia. JAMA Psychiatry. 2015;72:226–34.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Yin J, Barr AM, Ramos-Miguel A, Procyshyn RM. Antipsychotic induced dopamine supersensitivity psychosis: a comprehensive review. Curr Neuropharmacol. 2017;15:174–83.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Chen AT, Nasrallah HA. Neuroprotective effects of the second generation antipsychotics. Schizophr Res. 2019;208:1–7.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Bowling H, Santini E. Unlocking the molecular mechanisms of antipsychotics – a new frontier for discovery. Swiss Med Wkly. 2016;146:w14314.PubMedGoogle Scholar
  55. 55.
    Goff DC, Falkai P, Fleischhacker WW, Girgis RR, Kahn RM, Uchida H, et al. The long-term effects of antipsychotic medication on clinical course in schizophrenia. Am J Psychiatry. 2017;174:840–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry. 2013;70:913–20.CrossRefGoogle Scholar

Additional Resources

    Articles

    1. Freudenreich O. Dosing units help avoid medication errors [Pearl]. Curr Psychiatry. 2008;7:80–8. – From the Pearls Series, this one-page summary provides a simple scheme to remember typical dosing of antipsychotics, using clinical reference dosing units. This approach is helpful to spot unusual antipsychotic doses if you look over medications lists for example.Google Scholar
    2. Goff DC, Falkai P, Fleischhacker WW, Girgis RR, Kahn RM, Uchida H, et al. The long-term effects of antipsychotic medication on clinical course in schizophrenia. Am J Psychiatry. 2017;174:840–9. – Leaders in the field of schizophrenia research summarize what is known about antipsychotic neurotoxicity and the possible negative effects on the long-term course of illness.PubMedCrossRefGoogle Scholar
    3. Kontos N, Querques J, Freudenreich O. The problem of the psychopharmacologist. Acad Psychiatry. 2006;30:218–26. – Mandatory remedial reading if you consider yourself a “psychopharmacologist”.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Oliver Freudenreich
    • 1
  1. 1.Department of PsychiatryMassachusetts General HospitalBostonUSA

Personalised recommendations