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Pharmacological and Clinical Profile of Recently Approved Second-Generation Antipsychotics

Implications for Treatment of Schizophrenia in Older Patients

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Abstract

Antipsychotics are frequently used in elderly patients to treat a variety of conditions, including schizophrenia. While extensively studied for their impact in younger populations, there is comparatively limited evidence about the effectiveness of these agents in older patients. Further complicating this situation are the high comorbidity rates (both psychiatric and medical) in the elderly; age-related changes in pharmacokinetics that lead to a heightened proclivity for adverse effects; and the potential for multiple, clinically relevant drug interactions. With this background in mind, we review diagnostic and treatment-related issues specific to elderly patients suffering from schizophrenia. We then focus on the potential role of the most recently approved second-generation antipsychotics, paliperidone (both the extended-release oral formulation and the long-acting injectable formulation), iloperidone, asenapine and lurasidone, given the limited clinical experience with these agents in the elderly. While there is limited data to support their safety, tolerability and efficacy in older patients with schizophrenia, each has unique characteristics that should be considered when used in this population.

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References

  1. Rado J, Janicak PG. Schizophrenia. In: Rakel RE, Bope ET, editors. Conn’s current therapy 2009. Philadelphia: Saunders Elsevier; 2009.

    Google Scholar 

  2. Rabins PV, Black B, German P, et al. The prevalence of psychiatric disorders in elderly residents of public housing. J Gerontol A Biol Sci Med Sci. 1996;51(6):M319–24.

    Article  PubMed  CAS  Google Scholar 

  3. Girard C, Simard M. Clinical characterization of late- and very late-onset first psychotic episode in psychiatric inpatients. Am J Geriatr Psychiatr. 2008;16:478–87.

    Article  Google Scholar 

  4. Cohen CI. Studies of the outcome of schizophrenia in later life. Psychiatr Serv. 1995;46:877–9.

    PubMed  CAS  Google Scholar 

  5. Bartels SJ, Muser KT, Miles KM. Functional impairments in elderly patients with schizophrenia and major affective disorders living in the community: social skills, living skills and behaviour problems. Behav Ther. 1997;28:43–63.

    Article  Google Scholar 

  6. Klapow J, Evans J, Patterson TL, et al. Direct assessment of functional status in older patients with schizophrenia. Am J Psychiatr. 1997;154:1022–4.

    PubMed  CAS  Google Scholar 

  7. Patterson TL, Klapow JC, Eastham JH, et al. Correlates of functional status in older outpatients. Psychiatr Res. 1998;80:41–52.

    Article  CAS  Google Scholar 

  8. Gupta S, Steinmeyer CH, Lockwood K, et al. Comparison of older patients with bipolar disorder and schizophrenia/schizoaffective disorders. Am J Geriatr Psychiatr. 2007;15:627–33.

    Article  Google Scholar 

  9. Berry K, Barrowclough C. The needs of older adults with schizophrenia: implication for psychological interventions. Clin Psychol Rev. 2009;29:68–76.

    Article  PubMed  Google Scholar 

  10. Cohen CI. Age-related correlations in patient symptom management strategies in schizophrenia: an exploratory study. Int J Geriatr Psychiatr. 1993;8:211–3.

    Article  Google Scholar 

  11. Salano N, Krauss Whitbourne S. Coping with schizophrenia: patterns in later adulthood. Int J Aging Hum Dev. 2001;53:1–10.

    Article  Google Scholar 

  12. Howard R, Rabins PV, Seeman MV, Jeste DV, The International Late-Onset Schizophrenia Group. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. Am J Psychiatr. 2000;157(2):172–8.

    Article  PubMed  CAS  Google Scholar 

  13. Harvey PD, Friedman JI. Cognitive functioning in late-life schizophrenia. In: Cohen CI, editor. Schizophrenia into later life. Arlington, American Psychiatric Publishing; 1999.

  14. Kurtz MM. Neurocognitive impairment across the lifespan in schizophrenia: an update. Schizophr Res. 2005;74:15–26.

    Article  PubMed  Google Scholar 

  15. Jeste DV, Symonds LL, Harris MJ, et al. Non-dementia non-praecox dementia praecox? Late-onset schizophrenia. Am J Geriatr Psychiatr. 1997;5:302–17.

    Article  CAS  Google Scholar 

  16. Cuffel BJ, Jeste DV, Halpain M, et al. Treatment costs and use of community mental health services for schizophrenia by age-cohorts. Am J Psychiatr. 1996;153:870–6.

    PubMed  CAS  Google Scholar 

  17. Zisook S, McAdams LA, Kuck J, et al. Depressive symptoms in schizophrenia. Am J Psychiatr. 1999;156:1736–43.

    PubMed  CAS  Google Scholar 

  18. Jin H, Zisook S, Palmer B, et al. Association of depressive symptoms with worse functioning in schizophrenia: a study of older outpatients. J Clin Psychiatr. 2001;62:797–803.

    Article  CAS  Google Scholar 

  19. Meeks S, Woodruff-Borden J. Anxiety: comorbidity and impact in severe mental illness. J Clin Geropsychol. 1996;2:141–52.

    Google Scholar 

  20. Osby U, Correia N, Brandt L, et al. Mortality and causes of death in schizophrenia in Stockholm County, Sweden. Schizophr Res. 2000;45:21–8.

    Article  PubMed  CAS  Google Scholar 

  21. Howanitz E, Pardo M, Smelson DA, Engelhart C, Eisenstein N, Losonczy MF. The efficacy and safety of clozapine versus chlorpromazine in geriatric schizophrenia. J Clin Psychiatr. 1999;60(1):41–4.

    Article  CAS  Google Scholar 

  22. Kennedy JS, Jeste D, Kaiser CJ. Olanzapine vs haloperidol in geriatric schizophrenia: analysis of data from a double-blind controlled trial. Int J Geriatr Psychiatr. 2003;18:1013–20.

    Article  CAS  Google Scholar 

  23. Jeste DV, Barak Y, Madhusoodanan S, Grossman F, Gharabawi G. International multisite double-blind trial of the atypical antipsychotics risperidone and olanzapine in 175 elderly patients with chronic schizophrenia. Am J Geriatr Psychiatr. 2003;11:638–47.

    Google Scholar 

  24. Mazeh D, Paleacu D, Barak Y. Quetiapine for elderly non-responsive schizophrenia patients. Psychiatr Res. 2008;157:265–7.

    Article  CAS  Google Scholar 

  25. Wlodzimiewrz CK, Marcus RN, Tobeyns A, Nyilas M, McQuade RD. Effectiveness of long-term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a 52-week, open-label comparison with olanzapine. Psychopharmacology. 2006;189:259–66.

    Article  Google Scholar 

  26. Takeuchi H, Suzuki T, Uchida H, et al. A randomized, open-label comparison of 2 switching strategies to aripiprazole treatment in patients with schizophrenia. J Clin Psychopharmacol. 2008;28:540–3.

    Article  PubMed  CAS  Google Scholar 

  27. Madhusoodan S, Brenner R, Gupta S, Reddy H, Bogunovic O. Clinical experience with aripiprazole treatment in ten elderly patients with schizophrenia or schizoaffective disorder: retrospective case studies. CNS Spectr. 2004;9(11):862–7.

    Google Scholar 

  28. Shastri M, Alla L, Sabaratnam M. Aripiprazole use in individuals with intellectual disability and psychotic or behavioural disorders: a case series. J Psychopharmacol. 2006;20(6):863–7.

    Article  PubMed  Google Scholar 

  29. Ponde MP, Novaes CM. Aripiprazole worsening positive symptoms and meantime reducing negative symptoms in a patient with paranoid schizophrenia. Rev Bras Psiquiatr. 2007;28(1):86–95.

    Google Scholar 

  30. Carney C, Jones L, Woolson RF. Medical comorbidity in women and men with schizophrenia. J Gen Intern Med. 2006;21:1133–7.

    Article  PubMed  Google Scholar 

  31. Janicak PG, Marder S, Pavuluri M. Principles and practice of psychopharmacotherapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. p. 633–61.

    Google Scholar 

  32. Tzimos A, Samokhvalov V, Kramer M, et al. Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with long-term open-label extension. Am J Geriatr Psychiatr. 2008;16(1):31–43.

    Article  Google Scholar 

  33. INVEGA package insert. Prescribing information for paliperidone extended-release [online]. 2007. http://www.janssen.com. Accessed June 2007.

  34. Conley R, Gupta SK, Sathyan G. Clinical spectrum of the osmotic-controlled release oral delivery system (OROS®), and advanced oral delivery form. Curr Med Res Opin. 2005;22:1879–92.

    Article  Google Scholar 

  35. Gram S, Fitlon A. Risperidone: a review of its pharmacology and therapeutic potential in the treatment of schizophrenia. Drugs. 1994;48(2):253–73.

    Article  Google Scholar 

  36. Horacek J, Bubenikova-Valesova V, Kopecek M, et al. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs. 2006;20(5):389–409.

    Article  PubMed  CAS  Google Scholar 

  37. Karlsson P, Dencker E, Nyberg S, et al. Pharmacokinetics and dopamine D(2) and serotonin 5-HT(2A) receptor occupancy of paliperidone in healthy subjects [abstract no. P.1.053]. Eyr Neuropsychopharmacol. 2005;15(Suppl. 3):386. Plus poster presented at the 18th European College of Neuropsychopharmacology Congress; 2005 Oct 22–26; Amsterdam.

    Google Scholar 

  38. Leysen JE, Janssen PM, Megens AA, Schotte A. Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. J Clin Psychiatr. 1994;55(Suppl. 5):5–12.

    Google Scholar 

  39. Cleton A, Rossenu S, Vermeulen A, et al. A pharmacokinetic model to document the interconversion between paliperidone’s enantiomers [abstract no. PII-72]. Clin Pharmacol Ther. 2006;79(2):55.

    Article  Google Scholar 

  40. Yang LPH, Plosker GL. Paliperidone extended release. CNS Drugs. 2007;21(5):1172–7047.

    Article  Google Scholar 

  41. Rossenu S, Cleton A, Talluri K, et al. Evaluation of the pharmacokinetics of an extended-release formulation of paliperidone with an immediate-release formulation of risperidone. Clin Pharm Ther. 2007;81(Suppl. 1):S62.

    Google Scholar 

  42. Mannens G, Meuldermans W, Snoeck E, Heykants J. Plasma protein binding of risperidone and its distribution in blood. Psychopharmacology. 1994;114:566–72.

    Article  PubMed  CAS  Google Scholar 

  43. Vermeir M, Boom S, Naessens I, et al. Absorption, metabolism and excretion of a single oral dose of 14C-paliperidone 1 mg in healthy subjects. Eur Neuropsychopharmacol. 2005;30:S191–2.

    Google Scholar 

  44. Thyssen A, Cleton A, Talluri K, Leempoels J, Janssens L, Boom S, Eerdekens M. No pharmacokinetic interaction between paliperidone extended-release tablets and trimethoprim in healthy subjects. Hum Psychopharmacol. 2009;24(7):532–9.

    Article  PubMed  CAS  Google Scholar 

  45. Meltzer H, Kramer M, Gassmann-Mayer C, et al. Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week placebo controlled studies. Int J Neuropsychopharmacol. 2006;9:S225.

    Google Scholar 

  46. Janicak PG, Winans EA, Paliperidone ER. A review of the clinical trial data. Neuropsychiatr Dis Treat. 2007;3(6):1–15.

    Google Scholar 

  47. Hough DW, Natarajan J, Vandebosh A, et al. Evaluation of the effect of paliperidone extended release and quetiapine on corrected QT intervals: a randomized, double-blind, placebo-controlled study. Int Clin Psychopharmacol. 2011;26(1):25–34.

    Article  PubMed  Google Scholar 

  48. Knegtering R, Baselmans P, Castelein S, et al. Predominant role of the 9-hydroxy metabolite of risperidone in elevating blood prolactin levels. Am J Psychiatr. 2005;2005(162):1010–2.

    Article  Google Scholar 

  49. Boom S, Thyssen A, Crauwels H, et al. The influence of hepatic impairment on the pharmacokinetics of paliperidone. Int J Clin Pharmacol Ther. 2009;47(10):606–16.

    PubMed  CAS  Google Scholar 

  50. Thyssen A, Cleton A, Osselae NV. Effects of renal impairment on the pharmacokinetic profile of paliperidone extended-release tablets. Clin Pharm Ther. 2007;81(Suppl. 1):S63.

    Google Scholar 

  51. Samtani MN, Gopal S, Gassmann-Mayer C, Alphs L, Palumbo JM. Dosing and switching strategies for paliperidone palmitate: based on population pharmacokinetic modeling and clinical trial data. CNS Drugs. 2011;25(10):829–45.

    PubMed  CAS  Google Scholar 

  52. Samtani M, Sliwa JK, Haskins JT, et al. Initiation of dosing and deltoid intramuscular paliperidone palmitate in schizophrenia: pharmacokinetic rationale based on modeling and simulation. J Pharm Pract. 2009;22:216–7.

    Google Scholar 

  53. Hough D, Lindenmayer JP, Gopal S, et al. Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatr. 2009;33(6):1022–31.

    Article  CAS  Google Scholar 

  54. Samtani MN, Vermeulen A, Stuyckens K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia a novel once-monthly, long-acting formulation of an atypical antipsychotic. Clin Pharmacokinet. 2009;48(9):585–600.

    Article  PubMed  CAS  Google Scholar 

  55. Rado J, Janicak PG. A novel treatment option for schizophrenia. Psychopharm Rev. 2010;45(1):1–8.

    Google Scholar 

  56. Potkin SG, Litman RE, Torres R, et al. Efficacy of iloperidone in the treatment of schizophrenia: initial phase 3 studies. J Clin Psychopharmacol. 2008;28:S4–11.

    Article  PubMed  CAS  Google Scholar 

  57. Cutler AJ, Kalali AH, Weiden PJ, et al. Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol. 2008;28(2 Suppl. 1):S20–8.

    Article  PubMed  CAS  Google Scholar 

  58. Weiden PJ, Cutler AJ, Polymeropoulos MH, et al. Safety profile of iloperidone: a pooled analysis of 6-week acute-phase pivotal trials. J Clin Psychopharmacol. 2008;28(2 Suppl. 1):S12–9.

    Article  PubMed  CAS  Google Scholar 

  59. Ichikawa J, Li Z, Dai J, et al. Atypical antipsychotic drugs, quetiapine, iloperidone and melperidone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT1A receptor agonism. Brain Res. 2002;956:349–57.

    Article  PubMed  CAS  Google Scholar 

  60. Kalkman HO, Subramanian N, Hoyer D. Extended radioligand binding profile of iloperidone: a broad spectrum dopamine/serotonin norepinephrine receptor antagonist for the management of psychotic disorders. Neuropsychopharmacology. 2001;25:904–14.

    Article  PubMed  CAS  Google Scholar 

  61. Kalkman HO, Feuerbach D, Lotscher E. Functional characterization of the novel antipsychotic iloperidone at human D2, D3, alpha 2C, 5-HT6, and 5-HT1A receptors. Life Sci. 2003;73(9):1151–9.

    Article  PubMed  CAS  Google Scholar 

  62. FANAPT® (iloperidone) prescribing information. http://www.pharma.us.novartis.com/product/pi/pdf/fanapt.pdf. Accessed 16 Jan 2012.

  63. Subramanian N, Kalkman HO. Receptor profile of P88–8991 and P95–12113, metabolites of the novel antipsychotic iloperidone. Prog Neuropsychopharmacol Biol Psychiatr. 2002;26:553–60.

    Article  CAS  Google Scholar 

  64. Volpi S, Potkin SG, Malhotra AK, et al. Applicability of a genetic signature for enhanced iloperidone efficacy in the treatment of schizophrenia. J Clin Psychiatr. 2009;70(6):801–9.

    Article  CAS  Google Scholar 

  65. Volpi S, Heaton C, Mack K, et al. Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment in schizophrenia. Mol Psychiatr. 2009;14(11):1024–31.

    Article  CAS  Google Scholar 

  66. Dubovsky SL, Frobose C, Phiri P, et al. Short-term safety and pharmacokinetic profile of asenapine in older patients with psychosis. Int J Geriatr Psychiatr. 2012;27(5):472–82.

    Article  Google Scholar 

  67. Hulskotte E, Spaans E, Timmer C. Effects of water intake and smoking on the absorption of sublingually administered asenapine [abstract no. PIII-57]. Clin Pharmacol Ther. 2009;85(Suppl. 1):S20–8.

    Google Scholar 

  68. Janicak PG, Rado JT. Asenapine. a review of the data. Psychopharm Rev. 2009;44(12):89–96.

    Google Scholar 

  69. Shoemaker J, Naber D, Vrijland P, Panagides J, Emsley R. Long-term assessment of asenapine versus olanzapine in patients with schizophrenia or schizoaffective disorder. Pharmacopsychiatry. 2010;43:138–46.

    Article  Google Scholar 

  70. Chapel S, Hutmacher MM, Haig G, et al. Exposure-response analysis in patients with schizophrenia to assess the effect of asenapine on QTc prolongation. J Clin Pharmacol. 2009;49:1297–308.

    Article  PubMed  CAS  Google Scholar 

  71. Shahid M, Walker GB, Zorn SN, et al. Asenapine: a novel psychopharmacological agent with a unique human receptor signature. J Psychopharmacol. 2009;23(1):65–73.

    Article  PubMed  CAS  Google Scholar 

  72. ABILIFY® (aripiprazole) prescribing information. http://www.abilify.com/pdf/pi.aspx?tc=89340&utm_source=google&utm_medium=organic_search&utm_term=aripiprazole+prescribing+information&q=aripiprazole+prescribing+information&hl=en&source=hp&gs_sm=s&gs_upl=1375l1375l0l1828l1l1l0l0l0l0l0l0ll0l0&oq=aripiprazole+prescribing+information&aq=f&aqi=g1&aql=1. Accessed 25 Oct 2011.

  73. Peeters P, Bockbrader H, Spaans E, et al. Asenapine pharmacokinetics in hepatic and renal impairment. Clin Pharmacokinet. 2011;50(7):471–81.

    Article  PubMed  CAS  Google Scholar 

  74. Fayad SM, Tandon R. Lurasidone: the most recent addition to our antipsychotic armentarium: a review of the data. Psychopharm Rev. 2011;46(6):41–8.

    Google Scholar 

  75. Latuda prescribing information. http://www.latuda.com/aboutLatuda/taking-latuda.html. Accessed 25 Oct 2011.

  76. Meyer JM, Loebel AD, Schweizer E. Lurasidone: a new drug in development for schizophrenia. Expert Opin Investig Drugs. 2009;18(11):1715–26.

    Article  PubMed  CAS  Google Scholar 

  77. Nakamura M, Ogasa M, Guarino J, et al. Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatr. 2009;70(6):829–36.

    Article  CAS  Google Scholar 

  78. Harvey PD, Ogasa M, Cucchiaro J, et al. Performance and interview-based assessments of cognitive change in a randomized, double blind comparison of lurasidone vs. ziprasidone. Schizophrenia Res. 2011;127:188–94.

    Article  Google Scholar 

  79. Ishibashi T, Horisawa T, Tokuda K, et al. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxy-tryptamine 7 (5-HT7) and 5-HT1A receptor activity. J Pharmacol Exp Ther. 2010;334:171–81.

    Article  PubMed  CAS  Google Scholar 

  80. Guay DR. Comment on the potential utility of the new atypical antipsychotic lurasidone in the geriatric population. Consult Pharm. 2011;26(8):579–82.

    Article  PubMed  Google Scholar 

  81. Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Intl J Clin Pract. 2011;65(2):189–210.

    Article  CAS  Google Scholar 

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Acknowledgments

Dr. Rado receives Grant support from Otsuka, Cervel Neurotech, Inc., Neuronetics, Sunovion, and Janssen; and consulting fees from Alkermes. Dr. Janicak receives/received Grant support from Otsuka, Johnson and Johnson, Neuronetics, Cervel Neurotech, Sunovion; consulting fees or honorarium from Neuronetics; fees for participation in review activities from Novartis; payment for lectures including service on speaker’s bureaus from Bristol Meyers Squibb, Otsuka, and Neuronetics; and he receives royalties from Lippincott, Williams and Wilkins. Support for the preparation of this review came from Rush University Medical Center.

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  1. Psychiatric Clinical Research Center, Rush University Medical Center, 2150 West Harrison Street, Chicago, IL, 60612, USA

    Jeffrey Rado & Philip G. Janicak

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Correspondence to Jeffrey Rado.

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Rado, J., Janicak, P.G. Pharmacological and Clinical Profile of Recently Approved Second-Generation Antipsychotics . Drugs Aging 29, 783–791 (2012). https://doi.org/10.1007/s40266-012-0009-0

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