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CNS Drugs

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Achieving the Lowest Effective Antipsychotic Dose for Patients with Remitted Psychosis: A Proposed Guided Dose-Reduction Algorithm

  • Chen-Chung LiuEmail author
  • Hiroyoshi Takeuchi
Current Opinion

Abstract

Continuing antipsychotic treatment in patients with schizophrenia under clinical remission remains controversial. Even though the mainstream opinion declares an outweighed balance against medication discontinuation, recent reviews and critiques suggest that some patients may remain symptom free and well functioning after stopping antipsychotics, but few predictors can identify who can try medication discontinuation, whilst no guidelines exist for reducing medication to reach the lowest effective dose safely. Analyzing the findings from studies employing different methodologies, adopting evidence from pharmacodynamic research, and observing dose reduction in stable patients, as well as taking inspiration from the metaphor of the Cantor set in natural philosophy, we introduce an alternative solution and propose a guided dose-reduction algorithm that follows a set of clear precautions and instructions. The algorithm recommends only a fraction (no more than 25%) of the dosage to be reduced at a time, with at least a 6-month stabilization period required before reducing another 25% of the dose. Patients are empowered to actively participate in decision making when they are ready for further dose tapering, or should they retreat to a previous dosage if warning signs of a relapse re-emerge. An intermittent or irregular dosing schedule can be used to adapt this algorithm to real-world practice. Our preliminary findings suggest that patients with remitted psychosis can do well along this path. We anticipate that this approach can help optimize the risk–benefit ratio and instill a hope in patients with schizophrenia that they can maintain in stable remission under a lower antipsychotic dose without an increased risk of relapse.

Notes

Compliance with Ethical Standards

Funding

Chen-Chung Liu received research Grants MOST 106-2314-B-002-106 and MOST 107-2314-B-002-222-MY3 from the Ministry of Science and Technology, Taiwan. Chen-Chung Liu has also received speaker’s honoraria from Janssen-Cilag Pharma. Hiroyoshi Takeuchi has received research grants from the Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, and SENSHIN Medical Research Foundation. Hiroyoshi Takeuchi has also received speaker’s honoraria from Meiji-Seika Pharma, Mochida, Otsuka, Sumitomo Dainippon Pharma, and Yoshitomi Yakuhin, and manuscript fees from Sumitomo Dainippon Pharma. The funding sources did not participate in the preparation, review, approval, or decision to submit this manuscript for publication.

Conflict of interest

Chen-Chung Liu and Hiroyoshi Takeuchi have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the hospital’s research ethics committee (NTUHREC No. 201703002RIND) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

All participants provided written informed consent to participate.

References

  1. 1.
    Tsuang MT, Stone WS, Faraone SV. Towards the prevention of schizophrenia. Biol Psychiatry. 2000;48(5):349–56.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Yung AR, McGorry PD. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull. 1996;22(2):353–70.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Olsen KA, Rosenbaum B. Prospective investigations of the prodromal state of schizophrenia: review of studies. Acta Psychiatr Scand. 2006;113(4):247–72.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    McGlashan TH, Addington J, Cannon T, Heinimaa M, McGorry P, O’Brien M, et al. Recruitment and treatment practices for help-seeking “prodromal” patients. Schizophr Bull. 2007;33(3):715–26.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Keshavan MS, Haas G, Miewald J, Montrose DM, Reddy R, Schooler NR, et al. Prolonged untreated illness duration from prodromal onset predicts outcome in first episode psychoses. Schizophr Bull. 2003;29(4):757–69.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Larsen TK, Friis S, Haahr U, Joa I, Johannessen JO, Melle I, et al. Early detection and intervention in first-episode schizophrenia: a critical review. Acta Psychiatr Scand. 2001;103(5):323–34.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Malla AK, Norman RM, Manchanda R, Ahmed MR, Scholten D, Harricharan R, et al. One year outcome in first episode psychosis: influence of DUP and other predictors. Schizophr Res. 2002;54(3):231–42.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Lieberman JA, Alvir JM, Koreen A, Geisler S, Chakos M, Sheitman B, et al. Psychobiologic correlates of treatment response in schizophrenia. Neuropsychopharmacology. 1996;14(3 Suppl):13S–21S.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 2005;162(3):441–9.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Chang WC, Chan TC, Chen ES, Hui CL, Wong GH, Chan SK, et al. The concurrent and predictive validity of symptomatic remission criteria in first-episode schizophrenia. Schizophr Res. 2013;143(1):107–15.PubMedCrossRefGoogle Scholar
  11. 11.
    McGorry PD, Hickie IB, Yung AR, Pantelis C, Jackson HJ. Clinical staging of psychiatric disorders: a heuristic framework for choosing earlier, safer and more effective interventions. Aust N Z J Psychiatry. 2006;40(8):616–22.PubMedCrossRefGoogle Scholar
  12. 12.
    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(5):410–72.PubMedCrossRefGoogle Scholar
  13. 13.
    Correll CU, Rubio JM, Kane JM. What is the risk-benefit ratio of long-term antipsychotic treatment in people with schizophrenia? World Psychiatry. 2018;17(2):149–60.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Kane JM, Garcia-Ribera C. Clinical guideline recommendations for antipsychotic long-acting injections. Br J Psychiatry Suppl. 2009;195(52):S63–7.CrossRefGoogle Scholar
  15. 15.
    Takeuchi H, Suzuki T, Uchida H, Watanabe K, Mimura M. Antipsychotic treatment for schizophrenia in the maintenance phase: a systematic review of the guidelines and algorithms. Schizophr Res. 2012;134(2–3):219–25.PubMedCrossRefGoogle Scholar
  16. 16.
    Barnes TR. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2011;25(5):567–620.PubMedCrossRefGoogle Scholar
  17. 17.
    Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geisler S, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56(3):241–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Caseiro O, Perez-Iglesias R, Mata I, Martinez-Garcia O, Pelayo-Teran JM, Tabares-Seisdedos R, et al. Predicting relapse after a first episode of non-affective psychosis: a 3-year follow-up study. J Psychiatr Res. 2012;46(8):1099–105.PubMedCrossRefGoogle Scholar
  19. 19.
    Takeuchi H, Siu C, Remington G, Fervaha G, Zipursky R, Foussias G, et al. Does relapse contribute to treatment resistance? Antipsychotic response in first- vs. second-episode schizophrenia. Schizophr Bull. 2018;44(Suppl. 1):267.CrossRefGoogle Scholar
  20. 20.
    Emsley R, Nuamah I, Hough D, Gopal S. Treatment response after relapse in a placebo-controlled maintenance trial in schizophrenia. Schizophr Res. 2012;138(1):29–34.PubMedCrossRefGoogle Scholar
  21. 21.
    Wiersma D, Nienhuis FJ, Slooff CJ, Giel R. Natural course of schizophrenic disorders: a 15-year followup of a Dutch incidence cohort. Schizophr Bull. 1998;24(1):75–85.PubMedCrossRefGoogle Scholar
  22. 22.
    Gaebel W, Riesbeck M, Wolwer W, Klimke A, Eickhoff M, von Wilmsdorff M, et al. Relapse prevention in first-episode schizophrenia: maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry. 2011;72(2):205–18.PubMedCrossRefGoogle Scholar
  23. 23.
    Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry. 2007;68(5):654–61.PubMedCrossRefGoogle Scholar
  24. 24.
    Mayoral-van Son J, de la Foz VO, Martinez-Garcia O, Moreno T, Parrilla-Escobar M, Valdizan EM, et al. Clinical outcome after antipsychotic treatment discontinuation in functionally recovered first-episode nonaffective psychosis individuals: a 3-year naturalistic follow-up study. J Clin Psychiatry. 2016;77(4):492–500.PubMedCrossRefGoogle Scholar
  25. 25.
    Takeuchi H, Kantor N, Sanches M, Fervaha G, Agid O, Remington G. One-year symptom trajectories in patients with stable schizophrenia maintained on antipsychotics versus placebo: meta-analysis. Br J Psychiatry. 2017;211(3):137–43.PubMedCrossRefGoogle Scholar
  26. 26.
    De Hert M, Sermon J, Geerts P, Vansteelandt K, Peuskens J, Detraux J. The use of continuous treatment versus placebo or intermittent treatment strategies in stabilized patients with schizophrenia: a systematic review and meta-analysis of randomized controlled trials with first- and second-generation antipsychotics. CNS Drugs. 2015;29(8):637–58.PubMedCrossRefGoogle Scholar
  27. 27.
    Hui CLM, Honer WG, Lee EHM, Chang WC, Chan SKW, Chen ESM, et al. Long-term effects of discontinuation from antipsychotic maintenance following first-episode schizophrenia and related disorders: a 10 year follow-up of a randomised, double-blind trial. Lancet Psychiatry. 2018;5(5):432–42.PubMedCrossRefGoogle Scholar
  28. 28.
    Tiihonen J, Tanskanen A, Taipale H. 20-year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. Am J Psychiatry. 2018;175(8):765–73.PubMedCrossRefGoogle Scholar
  29. 29.
    Austin SF, Mors O, Secher RG, Hjorthoj CR, Albert N, Bertelsen M, et al. Predictors of recovery in first episode psychosis: the OPUS cohort at 10 year follow-up. Schizophr Res. 2013;150(1):163–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Morgan C, Lappin J, Heslin M, Donoghue K, Lomas B, Reininghaus U, et al. Reappraising the long-term course and outcome of psychotic disorders: the AESOP-10 study. Psychol Med. 2014;44(13):2713–26.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Ten Velden Hegelstad W, Haahr U, Larsen TK, Auestad B, Barder H, Evensen J, et al. Early detection, early symptom progression and symptomatic remission after ten years in a first episode of psychosis study. Schizophr Res. 2013;143(2–3):337–43.Google Scholar
  32. 32.
    Harrow M, Jobe TH, Faull RN. Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study. Psychol Med. 2012;42(10):2145–55.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Harrow M, Jobe TH, Faull RN, Yang J. A 20-year multi-followup longitudinal study assessing whether antipsychotic medications contribute to work functioning in schizophrenia. Psychiatry Res. 2017;256:267–74.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Wils RS, Gotfredsen DR, Hjorthoj C, Austin SF, Albert N, Secher RG, et al. Antipsychotic medication and remission of psychotic symptoms 10 years after a first-episode psychosis. Schizophr Res. 2017;182:42–8.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Liu CC, Lin YT, Liu CM, Hsieh MH, Chien YL, Hwang TJ, et al. Trajectories after first-episode psychosis: complement to ambiguous outcomes of long-term antipsychotic treatment by exploring a few hidden cases. Early Interv Psychiatry. 2019;13(4):895–901.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    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(9):913–20.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch Gen Psychiatry. 2011;68(2):128–37.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Fusar-Poli P, Smieskova R, Kempton MJ, Ho BC, Andreasen NC, Borgwardt S. Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neurosci Biobehav Rev. 2013;37(8):1680–91.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Haijma SV, Van Haren N, Cahn W, Koolschijn PC, Hulshoff Pol HE, Kahn RS. Brain volumes in schizophrenia: a meta-analysis in over 18,000 subjects. Schizophr Bull. 2013;39(5):1129–38.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Vita A, De Peri L, Deste G, Barlati S, Sacchetti E. The effect of antipsychotic treatment on cortical gray matter changes in schizophrenia: does the class matter? A meta-analysis and meta-regression of longitudinal magnetic resonance imaging studies. Biol Psychiatry. 2015;78(6):403–12.PubMedCrossRefGoogle Scholar
  41. 41.
    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(3):226–34.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Ho BC, Andreasen NC, Nopoulos P, Arndt S, Magnotta V, Flaum M. Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry. 2003;60(6):585–94.PubMedCrossRefGoogle Scholar
  43. 43.
    Kubota M, van Haren NE, Haijma SV, Schnack HG, Cahn W, Hulshoff Pol HE, et al. Association of IQ changes and progressive brain changes in patients with schizophrenia. JAMA Psychiatry. 2015;72(8):803–12.PubMedCrossRefGoogle Scholar
  44. 44.
    McGorry P, Alvarez-Jimenez M, Killackey E. Antipsychotic medication during the critical period following remission from first-episode psychosis: less is more. JAMA Psychiatry. 2013;70(9):898–900.PubMedCrossRefGoogle Scholar
  45. 45.
    Bowtell M, Ratheesh A, McGorry P, Killackey E, O’Donoghue B. Clinical and demographic predictors of continuing remission or relapse following discontinuation of antipsychotic medication after a first episode of psychosis. A systematic review. Schizophr Res. 2018;197:9–18.PubMedCrossRefGoogle Scholar
  46. 46.
    Alvarez-Jimenez M, Gleeson JF, Henry LP, Harrigan SM, Harris MG, Amminger GP, et al. Prediction of a single psychotic episode: a 7.5-year, prospective study in first-episode psychosis. Schizophr Res. 2011;125(2–3):236–46.PubMedCrossRefGoogle Scholar
  47. 47.
    Alvarez-Jimenez M, Priede A, Hetrick SE, Bendall S, Killackey E, Parker AG, et al. Risk factors for relapse following treatment for first episode psychosis: a systematic review and meta-analysis of longitudinal studies. Schizophr Res. 2012;139(1–3):116–28.PubMedCrossRefGoogle Scholar
  48. 48.
    Marder SR, Zito MF. Will I need to take these medications for the rest of my life? World Psychiatry. 2018;17(2):165–6.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Murray RM, Di Forti M. Increasing expectations and knowledge require a more subtle use of prophylactic antipsychotics. World Psychiatry. 2018;17(2):161–2.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Fleischhacker WW. The long-term treatment of schizophrenia with antipsychotics: a perennial debate. World Psychiatry. 2018;17(2):169–70.PubMedCrossRefGoogle Scholar
  51. 51.
    Keefe RS. Should cognitive impairment be included in the diagnostic criteria for schizophrenia? World Psychiatry. 2008;7(1):22–8.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008;371(9618):1085–97.PubMedCrossRefGoogle Scholar
  53. 53.
    McEvoy JP, Lieberman JA, Perkins DO, Hamer RM, Gu H, Lazarus A, et al. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry. 2007;164(7):1050–60.PubMedCrossRefGoogle Scholar
  54. 54.
    Cooper D, Moisan J, Gregoire JP. Adherence to atypical antipsychotic treatment among newly treated patients: a population-based study in schizophrenia. J Clin Psychiatry. 2007;68(6):818–25.PubMedCrossRefGoogle Scholar
  55. 55.
    Bowtell M, Eaton S, Thien K, Bardell-Williams M, Downey L, Ratheesh A, et al. Rates and predictors of relapse following discontinuation of antipsychotic medication after a first episode of psychosis. Schizophr Res. 2018;195:231–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Sampson S, Joshi K, Mansour M, Adams CE. Intermittent drug techniques for schizophrenia. Schizophr Bull. 2013;39(5):960–1.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Perkins DO, Gu H, Weiden PJ, McEvoy JP, Hamer RM, Lieberman JA. Predictors of treatment discontinuation and medication nonadherence in patients recovering from a first episode of schizophrenia, schizophreniform disorder, or schizoaffective disorder: a randomized, double-blind, flexible-dose, multicenter study. J Clin Psychiatry. 2008;69(1):106–13.PubMedCrossRefGoogle Scholar
  58. 58.
    Thompson A, Singh S, Birchwood M. Views of early psychosis clinicians on discontinuation of antipsychotic medication following symptom remission in first episode psychosis. Early Interv Psychiatry. 2016;10(4):355–61.PubMedCrossRefGoogle Scholar
  59. 59.
    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(9831):2063–71.PubMedCrossRefGoogle Scholar
  60. 60.
    Emsley R. Antipsychotic maintenance treatment in schizophrenia and the importance of preventing relapse. World Psychiatry. 2018;17(2):168–9.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Harrow M, Jobe TH. Long-term antipsychotic treatment of schizophrenia: does it help or hurt over a 20-year period? World Psychiatry. 2018;17(2):162–3.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Isohanni M, Miettunen J, Jaaskelainen E, Moilanen J, Hulkko A, Huhtaniska S. Under-utilized opportunities to optimize medication management in long-term treatment of schizophrenia. World Psychiatry. 2018;17(2):172–3.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Takeuchi H, Suzuki T, Uchida H, Kikuchi T, Nakajima S, Manki H, et al. How long to wait before reducing antipsychotic dosage in stabilized patients with schizophrenia? A retrospective chart review. J Psychiatr Res. 2011;45(8):1083–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Chen EY, Hui CL, Lam MM, Chiu CP, Law CW, Chung DW, et al. Maintenance treatment with quetiapine versus discontinuation after 1 year of treatment in patients with remitted first episode psychosis: randomised controlled trial. BMJ. 2010;341:c4024.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Emsley R, Oosthuizen PP, Koen L, Niehaus DJ, Martinez G. Symptom recurrence following intermittent treatment in first-episode schizophrenia successfully treated for 2 years: a 3-year open-label clinical study. J Clin Psychiatry. 2012;73(4):e541–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Chouinard G, Samaha AN, Chouinard VA, Peretti CS, Kanahara N, Takase M, et al. Antipsychotic-induced dopamine supersensitivity psychosis: pharmacology, criteria, and therapy. Psychother Ppsychosom. 2017;86(4):189–219.CrossRefGoogle Scholar
  67. 67.
    Gordon JH, Clopton JK, Curtin JC, Koller WC. Chronic autoreceptor blockade and neuroleptic-induced dopamine receptor hypersensitivity. Pharmacol Biochem Behav. 1987;26(2):223–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Kapur S, Mizrahi R, Li M. From dopamine to salience to psychosis: linking biology, pharmacology and phenomenology of psychosis. Schizophr Res. 2005;79(1):59–68.PubMedCrossRefGoogle Scholar
  69. 69.
    Remington G, Agid O, Foussias G, Fervaha G, Takeuchi H, Lee J, et al. What does schizophrenia teach us about antipsychotics? Can J Psychiatry. 2015;60(3 Suppl. 2):S14–8.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Remington G, Seeman P, Feingold A, Mann S, Shammi C, Kapur S. “Extended” antipsychotic dosing in the maintenance treatment of schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry. 2011;72(8):1042–8.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Brotzge K, Manshadi M, El-Mallakh RS. Intermittent aripiprazole for schizophrenia. Schizophr Res. 2012;134(2–3):302–3.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Tsuboi T, Suzuki T, Bies RR, Remington G, Pollock BG, Mimura M, et al. Challenging the need for sustained blockade of dopamine D(2) receptor estimated from antipsychotic plasma levels in the maintenance treatment of schizophrenia: a single-blind, randomized, controlled study. Schizophr Res. 2015;164(1–3):149–54.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Graff-Guerrero A, Rajji TK, Mulsant BH, Nakajima S, Caravaggio F, Suzuki T, et al. Evaluation of antipsychotic dose reduction in late-life schizophrenia: a prospective dopamine D2/3 receptor occupancy study. JAMA Psychiatry. 2015;72(9):927–34.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Ikai S, Remington G, Suzuki T, Takeuchi H, Tsuboi T, Den R, et al. A cross-sectional study of plasma risperidone levels with risperidone long-acting injectable: implications for dopamine D2 receptor occupancy during maintenance treatment in schizophrenia. J Clin Psychiatry. 2012;73(8):1147–52.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Mizuno Y, Bies RR, Remington G, Mamo DC, Suzuki T, Pollock BG, et al. Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: a cross-sectional study. Prog Neuropsychopharmacol Biol Psychiatry. 2012;37(1):182–7.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Moriguchi S, Bies RR, Remington G, Suzuki T, Mamo DC, Watanabe K, et al. Estimated dopamine D(2) receptor occupancy and remission in schizophrenia: analysis of the CATIE data. J Clin Psychopharmacol. 2013;33(5):682–5.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Takeuchi H, Suzuki T, Bies RR, Remington G, Watanabe K, Mimura M, et al. Dose reduction of risperidone and olanzapine and estimated dopamine D(2) receptor occupancy in stable patients with schizophrenia: findings from an open-label, randomized, controlled study. J Clin Psychiatry. 2014;75(11):1209–14.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Uchida H, Mamo DC, Kapur S, Labelle A, Shammi C, Mannaert EJ, et al. Monthly administration of long-acting injectable risperidone and striatal dopamine D2 receptor occupancy for the management of schizophrenia. J Clin Psychiatry. 2008;69(8):1281–6.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Uchida H, Suzuki T. Dose and dosing frequency of long-acting injectable antipsychotics: a systematic review of PET and SPECT data and clinical implications. J Clin Psychopharmacol. 2014;34(6):728–35.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Uchida H, Suzuki T, Graff-Guerrero A, Mulsant BH, Pollock BG, Arenovich T, et al. Therapeutic window for striatal dopamine D2/3 receptor occupancy in older patients with schizophrenia: a Pilot PET study. Am J Geriatr Psychiatry. 2014;22:1007–16.PubMedCrossRefGoogle Scholar
  81. 81.
    Takeuchi H, Suzuki T, Remington G, Bies RR, Abe T, Graff-Guerrero A, et al. Effects of risperidone and olanzapine dose reduction on cognitive function in stable patients with schizophrenia: an open-label, randomized, controlled, pilot study. Schizophr Bull. 2013;39(5):993–8.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Zhou Y, Li G, Li D, Cui H, Ning Y. Dose reduction of risperidone and olanzapine can improve cognitive function and negative symptoms in stable schizophrenic patients: a single-blinded, 52-week, randomized controlled study. J Psychopharmacol. 2018;32(5):524–32.PubMedCrossRefGoogle Scholar
  83. 83.
    Ferreiros J. The motives behind Cantor’s set theory: physical, biological, and philosophical questions. Sci Context. 2004;17(1–2):49–83.PubMedCrossRefGoogle Scholar
  84. 84.
    Bustillo J, Buchanan RW, Carpenter WT Jr. Prodromal symptoms vs. early warning signs and clinical action in schizophrenia. Schizophr Bull. 1995;21(4):553–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Leucht S. Is there compelling evidence that schizophrenia long-term treatment guidelines should be changed? World Psychiatry. 2018;17(2):166–7.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Millan MJ, Andrieux A, Bartzokis G, Cadenhead K, Dazzan P, Fusar-Poli P, et al. Altering the course of schizophrenia: progress and perspectives. Nat Rev Drug Discov. 2016;15(7):485–515.PubMedCrossRefGoogle Scholar
  87. 87.
    Garay RP, Citrome L, Samalin L, Liu CC, Thomsen MS, Correll CU, et al. Therapeutic improvements expected in the near future for schizophrenia and schizoaffective disorder: an appraisal of phase III clinical trials of schizophrenia-targeted therapies as found in US and EU clinical trial registries. Expert Opin Pharmacother. 2016;17(7):921–36.PubMedCrossRefGoogle Scholar
  88. 88.
    Alvarez-Jimenez M, O’Donoghue B, Thompson A, Gleeson JF, Bendall S, Gonzalez-Blanch C, et al. Beyond clinical remission in first episode psychosis: thoughts on antipsychotic maintenance vs. guided discontinuation in the functional recovery era. CNS Drugs. 2016;30(5):357–68.PubMedCrossRefGoogle Scholar
  89. 89.
    Sturup AE, Jensen HD, Dolmer S, Birk M, Albert N, Nielsen M, et al. TAILOR: tapered discontinuation versus maintenance therapy of antipsychotic medication in patients with newly diagnosed schizophrenia or persistent delusional disorder in remission of psychotic symptoms: study protocol for a randomized clinical trial. Trials. 2017;18(1):445.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Weller A, Gleeson J, Alvarez-Jimenez M, McGorry P, Nelson B, Allott K, et al. Can antipsychotic dose reduction lead to better functional recovery in first-episode psychosis? A randomized controlled-trial of antipsychotic dose reduction. The reduce trial: study protocol. Early Interv Psychiatry. 2018.  https://doi.org/10.1111/eip.12769(Epub ahead of print).CrossRefPubMedGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PsychiatryNational Taiwan University HospitalTaipeiTaiwan
  2. 2.Department of Psychiatry, College of MedicineNational Taiwan UniversityTaipeiTaiwan
  3. 3.Department of NeuropsychiatryKeio University School of MedicineTokyoJapan
  4. 4.Schizophrenia ProgramCentre for Addiction and Mental HealthTorontoCanada

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