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Clozapine response trajectories and predictors of non-response in treatment-resistant schizophrenia: a chart review study

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Abstract

Although clozapine is the main antipsychotic medication for treatment-resistant schizophrenia, 40–70% of patients on clozapine have persistent psychotic symptoms (i.e. ultra-treatment-resistant schizophrenia, UTRS). We aimed to examine clozapine response/non-response patterns in patients with treatment-resistant schizophrenia, as well as determine patient clinico-demographic factors associated with long-term clozapine non-response. Clinico-demographic characteristics of 241 patients on clozapine were collected through a retrospective chart review. The median (interquartile range, IQR) follow-up from illness onset was 25.0 (IQR = 24.0) years. Clozapine response was assessed at median 10.8 (IQR = 14.0) months (Time 1, T1) and 7.2 (IQR = 13.5) years (Time 2, T2) after its initiation. It was evaluated by chart reviewers based on the information provided in clinical notes. Binomial logistic regression was used to determine clinico-demographic factors associated with clozapine non-response at both T1 and T2 (i.e. stable UTRS, S-UTRS) compared to clozapine response at both times (i.e. stable clozapine responders, S-ClozResp). Among clozapine responders (n = 122) at T1, 83.6% remained clozapine responsive and 16.4% became non-responsive at T2. In the UTRS group (n = 119) at T1, 87.4% remained clozapine non-responsive and 12.6% became responsive at T2. Duration of delay in clozapine initiation (OR = 0.94, Wald χ2 = 5.33, p = 0.021) and number of pre-clozapine hospitalizations (OR = 0.95, Wald χ2 = 5.20, p = 0.023) were associated with S-UTRS. Most UTRS patients were non-responsive to clozapine from the start of treatment. Preventing delay in initiating clozapine and relapses could help promote long-term clozapine response in patients with treatment-resistant schizophrenia. Future longitudinal studies are required to explore the neuropathological correlates of relapses and delay in clozapine initiation.

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References

  1. Lally J, Gaughran F (2018) Treatment resistant schizophrenia: review and a call to action. Ir J Psychol Med. https://doi.org/10.1017/ipm.2018.47

    Article  PubMed  Google Scholar 

  2. Howes OD, McCutcheon R, Agid O et al (2017) Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology. Am J Psychiatry 174:216–229. https://doi.org/10.1176/appi.ajp.2016.16050503

    Article  PubMed  Google Scholar 

  3. Šagud M (2015) Treatment-resistant schizophrenia: challenges and implications for clinical practice. Psychiatr Danub 27:319–326

    PubMed  Google Scholar 

  4. Siskind D, Siskind V, Kisely S (2017) Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. Can J Psychiatry Rev Can Psychiatr 62:772–777. https://doi.org/10.1177/0706743717718167

    Article  Google Scholar 

  5. Semiz UB, Cetin M, Basoglu C et al (2007) Clinical predictors of therapeutic response to clozapine in a sample of Turkish patients with treatment-resistant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 31:1330–1336. https://doi.org/10.1016/j.pnpbp.2007.06.002

    Article  CAS  PubMed  Google Scholar 

  6. Thien K, Bowtell M, Eaton S et al (2018) Clozapine use in early psychosis. Schizophr Res 199:374–379. https://doi.org/10.1016/j.schres.2018.02.054

    Article  PubMed  Google Scholar 

  7. Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796

    Article  CAS  Google Scholar 

  8. Chung C, Remington G (2005) Predictors and markers of clozapine response. Psychopharmacology 179:317–335. https://doi.org/10.1007/s00213-005-2174-x

    Article  CAS  PubMed  Google Scholar 

  9. Suzuki T, Remington G, Mulsant BH et al (2011) Treatment resistant schizophrenia and response to antipsychotics: a review. Schizophr Res 133:54–62. https://doi.org/10.1016/j.schres.2011.09.016

    Article  PubMed  Google Scholar 

  10. Lieberman JA, Safferman AZ, Pollack S et al (1994) Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 151:1744–1752. https://doi.org/10.1176/ajp.151.12.1744

    Article  CAS  PubMed  Google Scholar 

  11. Schall U, Catts SV, Karayanidis F, Ward PB (1999) Auditory event-related potential indices of fronto-temporal information processing in schizophrenia syndromes: valid outcome prediction of clozapine therapy in a three-year follow-up. Int J Neuropsychopharmacol 2:83–93. https://doi.org/10.1017/S1461145799001418

    Article  PubMed  Google Scholar 

  12. Rosenheck R, Cramer J, Xu W et al (1997) A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. J Med 337:809–815

    CAS  Google Scholar 

  13. Umbricht DS, Wirshing WC, Wirshing DA et al (2002) Clinical predictors of response to clozapine treatment in ambulatory patients with schizophrenia. J Clin Psychiatry 63:420–424

    Article  Google Scholar 

  14. Fenton WS, Lee B (1993) Can clozapine response be predicted? A naturalistic pilot study. J Nerv Ment Dis 181:62–64

    Article  CAS  Google Scholar 

  15. Honer WG, MacEwan GW, Kopala L et al (1995) A clinical study of clozapine treatment and predictors of response in a Canadian sample. Can J Psychiatry Rev Can Psychiatr 40:208–211

    Article  CAS  Google Scholar 

  16. Ciapparelli A, Dell’Osso L, Bandettini di Poggio A et al (2003) Clozapine in treatment-resistant patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: a naturalistic 48-month follow-up study. J Clin Psychiatry 64:451–458

    Article  CAS  Google Scholar 

  17. McElroy SL, Dessain EC, Pope HG et al (1991) Clozapine in the treatment of psychotic mood disorders, schizoaffective disorder, and schizophrenia. J Clin Psychiatry 52:411–414

    CAS  PubMed  Google Scholar 

  18. Ciapparelli A, Ducci F, Carmassi C et al (2004) Predictors of response in a sample of treatment-resistant psychotic patients on clozapine. Eur Arch Psychiatry Clin Neurosci 254:343–346. https://doi.org/10.1007/s00406-004-0511-4

    Article  PubMed  Google Scholar 

  19. Pickar D, Owen RR, Litman RE et al (1994) Predictors of clozapine response in schizophrenia. J Clin Psychiatry 55(Suppl B):129–132

    PubMed  Google Scholar 

  20. Agid O, Arenovich T, Sajeev G et al (2011) An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 72:1439–1444. https://doi.org/10.4088/JCP.09m05785yel

    Article  PubMed  Google Scholar 

  21. Demjaha A, Egerton A, Murray RM et al (2014) Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry 75:e11–e13. https://doi.org/10.1016/j.biopsych.2013.06.011

    Article  CAS  PubMed  Google Scholar 

  22. Lally J, Ajnakina O, Di Forti M et al (2016) Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychol Med 46:3231–3240. https://doi.org/10.1017/S0033291716002014

    Article  CAS  PubMed  Google Scholar 

  23. Marshall M, Lewis S, Lockwood A et al (2005) Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry 62:975–983. https://doi.org/10.1001/archpsyc.62.9.975

    Article  PubMed  Google Scholar 

  24. Penttilä M, Jääskeläinen E, Hirvonen N et al (2014) Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis. Br J Psychiatry 205:88–94. https://doi.org/10.1192/bjp.bp.113.127753

    Article  PubMed  Google Scholar 

  25. Warnez S, Alessi-Severini S (2014) Clozapine: a review of clinical practice guidelines and prescribing trends. BMC Psychiatry 14:102. https://doi.org/10.1186/1471-244X-14-102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sharma A (2018) Maintenance doses for clozapine: past and present. BJPsych Bull 42:217. https://doi.org/10.1192/bjb.2018.64

    Article  PubMed  PubMed Central  Google Scholar 

  27. Simpson GM, Josiassen RC, Stanilla JK et al (1999) Double-blind study of clozapine dose response in chronic schizophrenia. Am J Psychiatry 156:1744–1750. https://doi.org/10.1176/ajp.156.11.1744

    Article  CAS  PubMed  Google Scholar 

  28. Guy W (1976) ECDEU assessment manual for psychopharmacology. National Institute of Mental Health Psychopharmacology. Research Branch, Department of Health, Education and Welfare, Rockville

    Google Scholar 

  29. Nielsen J, Nielsen R, Correll C (2012) Predictors of clozapine response in patients with treatment-refractory schizophrenia: results from a Danish Register Study. J Clin Psychopharmacol 32:678–683. https://doi.org/10.1097/JCP.0b013e318267b3cd

    Article  CAS  PubMed  Google Scholar 

  30. Agid O, Seeman P, Kapur S (2006) The “delayed onset” of antipsychotic action–an idea whose time has come and gone. J Psychiatry Neurosci JPN 31:93–100

    PubMed  Google Scholar 

  31. Carbon M, Correll CU (2014) Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues Clin Neurosci 16:505–524

    PubMed  PubMed Central  Google Scholar 

  32. Farooq S, Agid O, Foussias G, Remington G (2013) Using treatment response to subtype schizophrenia: proposal for a new paradigm in classification. Schizophr Bull 39:1169–1172. https://doi.org/10.1093/schbul/sbt137

    Article  PubMed  PubMed Central  Google Scholar 

  33. Samara MT, Nikolakopoulou A, Salanti G, Leucht S (2018) How many patients with schizophrenia do not respond to antipsychotic drugs in the short term? An analysis based on individual patient data from randomized controlled trials. Schizophr Bull. https://doi.org/10.1093/schbul/sby095

    Article  Google Scholar 

  34. Samara MT, Leucht C, Leeflang MM et al (2015) Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review. Am J Psychiatry 172:617–629. https://doi.org/10.1176/appi.ajp.2015.14101329

    Article  PubMed  Google Scholar 

  35. Meltzer HY (1997) Treatment-resistant schizophrenia–the role of clozapine. Curr Med Res Opin 14:1–20. https://doi.org/10.1185/03007999709113338

    Article  CAS  PubMed  Google Scholar 

  36. Demjaha A, Lappin JM, Stahl D et al (2017) Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors. Psychol Med 47:1981–1989. https://doi.org/10.1017/S0033291717000435

    Article  CAS  PubMed  Google Scholar 

  37. Shah P, Iwata Y, Plitman E et al (2018) The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: a systematic review. Psychiatry Res 268:114–122. https://doi.org/10.1016/j.psychres.2018.06.070

    Article  CAS  PubMed  Google Scholar 

  38. Harrison J, Janlöv M, Wheeler AJ (2010) Patterns of clozapine prescribing in a mental health service in New Zealand. Pharm World Sci 32:503–511. https://doi.org/10.1007/s11096-010-9398-5

    Article  PubMed  Google Scholar 

  39. Üçok A, Çkrkçl U, Karabulut S et al (2015) Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia. Int Clin Psychopharmacol 30(5):290–295. https://doi.org/10.1097/YIC.0000000000000086

    Article  PubMed  Google Scholar 

  40. Yada Y, Yoshimura B, Kishi Y (2015) Correlation between delay in initiating clozapine and symptomatic improvement. Schizophr Res 168:585–586. https://doi.org/10.1016/j.schres.2015.07.045

    Article  PubMed  Google Scholar 

  41. Yoshimura B, Yada Y, So R et al (2017) The critical treatment window of clozapine in treatment-resistant schizophrenia: secondary analysis of an observational study. Psychiatry Res 250:65–70. https://doi.org/10.1016/j.psychres.2017.01.064

    Article  CAS  PubMed  Google Scholar 

  42. Ucok A, Cikrikcili U, Karabulut S et al (2015) Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia. Int Clin Psychopharmacol 30:290–295

    Article  Google Scholar 

  43. ElGamal M, ElTayebani M, Fathi S (2013) Schizophrenia resistance (is there a difference?). Egypt J Psychiatry 34:51. https://doi.org/10.7123/01.EJP.0000415775.84252.a9

    Article  Google Scholar 

  44. Emsley R, Chiliza B, Asmal L, Harvey BH (2013) The nature of relapse in schizophrenia. BMC Psychiatry 13:50. https://doi.org/10.1186/1471-244X-13-50

    Article  PubMed  PubMed Central  Google Scholar 

  45. Takeuchi H, Siu C, Remington G et al (2018) Does relapse contribute to treatment resistance? Antipsychotic response in first- vs. second-episode schizophrenia. Neuropsychopharmacology. https://doi.org/10.1038/s41386-018-0278-3

    Article  PubMed  Google Scholar 

  46. Dammak M (2013) Treatment-resistant schizophrenia: prevalence and risk factors. In: Woolfolk R (ed) Mental disorders: theoretical and empirical perspectives. InTech, London

    Google Scholar 

  47. Gupta S, Kulhara P (2010) What is schizophrenia: a neurodevelopmental or neurodegenerative disorder or a combination of both? A critical analysis. Indian J Psychiatry 52:21–27. https://doi.org/10.4103/0019-5545.58891

    Article  PubMed  PubMed Central  Google Scholar 

  48. Plitman E, Nakajima S, de la Fuente-Sandoval C et al (2014) Glutamate-mediated excitotoxicity in schizophrenia: a review. Eur Neuropsychopharmacol 24:1591–1605. https://doi.org/10.1016/j.euroneuro.2014.07.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Remington G, Foussias G, Agid O et al (2014) The neurobiology of relapse in schizophrenia. Schizophr Res 152:381–390. https://doi.org/10.1016/j.schres.2013.10.009

    Article  PubMed  Google Scholar 

  50. Wu C-S, Wang S-C, Liu S-K (2015) Clozapine use reduced psychiatric hospitalization and emergency room visits in patients with bipolar disorder independent of improved treatment regularity in a three-year follow-up period. Bipolar Disord 17:415–423. https://doi.org/10.1111/bdi.12261

    Article  CAS  PubMed  Google Scholar 

  51. Sendt K-V, Giaroli G, Tracy DK (2012) Beyond dopamine: glutamate as a target for future antipsychotics. ISRN Pharmacol 2012:1–9. https://doi.org/10.5402/2012/427267

    Article  CAS  Google Scholar 

  52. van Haren NEM, Schnack HG, Cahn W et al (2011) Changes in cortical thickness during the course of illness in schizophrenia. Arch Gen Psychiatry 68:871–880. https://doi.org/10.1001/archgenpsychiatry.2011.88

    Article  PubMed  Google Scholar 

  53. Altamura AC, Pozzoli S, Fiorentini A, Dell’osso B (2013) Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology. Prog Neuropsychopharmacol Biol Psychiatry 42:63–70. https://doi.org/10.1016/j.pnpbp.2012.08.015

    Article  CAS  PubMed  Google Scholar 

  54. Keshavan MS (1999) Development, disease and degeneration in schizophrenia: a unitary pathophysiological model. J Psychiatr Res 33:513–521

    Article  CAS  Google Scholar 

  55. Ringbäck Weitoft G, Berglund M, Lindström EA et al (2014) Mortality, attempted suicide, re-hospitalisation and prescription refill for clozapine and other antipsychotics in Sweden-a register-based study. Pharmacoepidemiol Drug Saf 23:290–298. https://doi.org/10.1002/pds.3567

    Article  CAS  PubMed  Google Scholar 

  56. Chalasani L, Kant R, Chengappa KN (2001) Clozapine impact on clinical outcomes and aggression in severely ill adolescents with childhood-onset schizophrenia. Can J Psychiatry Rev Can Psychiatr 46:965–968. https://doi.org/10.1177/070674370104601010

    Article  CAS  Google Scholar 

  57. Kahn RS, Sommer IE, Murray RM et al (2015) Schizophrenia. Nat Rev Dis Primer 1:15067. https://doi.org/10.1038/nrdp.2015.67

    Article  Google Scholar 

  58. Owen Sawa A, Mortensen PB (2016) Schizophrenia. The Lancet 388:86–97. https://doi.org/10.1016/S0140-6736(15)01121-6

    Article  Google Scholar 

  59. Brunelin J, d’Amato T, van Os J et al (2008) Effects of acute metabolic stress on the dopaminergic and pituitary-adrenal axis activity in patients with schizophrenia, their unaffected siblings and controls. Schizophr Res 100:206–211. https://doi.org/10.1016/j.schres.2007.11.009

    Article  PubMed  Google Scholar 

  60. Graff-Guerrero A, Rajji TK, Mulsant BH et al (2015) Evaluation of antipsychotic dose reduction in late-life schizophrenia: a prospective dopamine D2/3 receptor occupancy study. JAMA Psychiatry 72:927–934. https://doi.org/10.1001/jamapsychiatry.2015.0891

    Article  PubMed  Google Scholar 

  61. Jeste DV, Maglione JE (2013) Treating older adults with schizophrenia: challenges and opportunities. Schizophr Bull 39:966–968. https://doi.org/10.1093/schbul/sbt043

    Article  PubMed  PubMed Central  Google Scholar 

  62. Jeste DV, Wolkowitz OM, Palmer BW (2011) Divergent trajectories of physical, cognitive, and psychosocial aging in schizophrenia. Schizophr Bull 37:451–455. https://doi.org/10.1093/schbul/sbr026

    Article  PubMed  PubMed Central  Google Scholar 

  63. Sajatovic M, Ramirez LF, Garver D et al (1998) Clozapine therapy for older veterans. Psychiatr Serv Wash DC 49:340–344. https://doi.org/10.1176/ps.49.3.340

    Article  CAS  Google Scholar 

  64. Marsman A, van den Heuvel MP, Klomp DWJ et al (2013) Glutamate in schizophrenia: a focused review and meta-analysis of 1H-MRS studies. Schizophr Bull 39:120–129. https://doi.org/10.1093/schbul/sbr069

    Article  PubMed  Google Scholar 

  65. Iwata Y, Nakajima S, Plitman E et al (2018) Glutamatergic neurometabolite levels in patients with ultra-treatment-resistant schizophrenia: a cross-sectional 3T proton magnetic resonance spectroscopy study. Biol Psychiatry. https://doi.org/10.1016/j.biopsych.2018.09.009

    Article  PubMed  Google Scholar 

  66. Nakajima S, Takeuchi H, Plitman E et al (2015) Neuroimaging findings in treatment-resistant schizophrenia: a systematic review. Schizophr Res 164:164–175. https://doi.org/10.1016/j.schres.2015.01.043

    Article  PubMed  PubMed Central  Google Scholar 

  67. Heresco-Levy U (2003) Glutamatergic neurotransmission modulation and the mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 27:1113–1123. https://doi.org/10.1016/j.pnpbp.2003.09.007

    Article  CAS  PubMed  Google Scholar 

  68. Lidsky TI, Yablonsky-Alter E, Zuck L, Banerjee SP (1993) Anti-glutamatergic effects of clozapine. Neurosci Lett 163:155–158. https://doi.org/10.1016/0304-3940(93)90370-Z

    Article  CAS  PubMed  Google Scholar 

  69. Chouinard G, Jones BD (1980) Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics. Am J Psychiatry 137:16–21. https://doi.org/10.1176/ajp.137.1.16

    Article  CAS  PubMed  Google Scholar 

  70. Ozkan S, Soydan A, Tamam L (2012) Supersensitivity psychosis in a case with clozapine tolerance. Eur Rev Med Pharmacol Sci 16:70–73

    Google Scholar 

  71. Ming L (2016) Antipsychotic-induced sensitization and tolerance: Behavioral characteristics, developmental impacts, and neurobiological mechanisms. J Psychopharmacol 30(8):749–770

    Article  Google Scholar 

  72. Chouinard G, Chouinard V-A (2008) Atypical Antipsychotics: CATIE Study, Drug-Induced Movement Disorder and Resulting Iatrogenic Psychiatric-Like Symptoms, Supersensitivity Rebound Psychosis and Withdrawal Discontinuation Syndromes. Psychother Psychosom 77:69–77. https://doi.org/10.1159/000112883

    Article  PubMed  Google Scholar 

  73. Ekblom B, Eriksson K, Lindstrom LH (1984) Supersensitivity psychosis in schizophrenic patients after sudden clozapine withdrawal. Psychopharmacology 83:293–294

    Article  CAS  Google Scholar 

  74. Moncrieff J (2006) Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand 114:3–13. https://doi.org/10.1111/j.1600-0447.2006.00787.x

    Article  CAS  PubMed  Google Scholar 

  75. Van Tol HH, Bunzow JR, Guan HC et al (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614. https://doi.org/10.1038/350610a0

    Article  PubMed  Google Scholar 

  76. Meltzer HY (1997) Clozapine withdrawal: serotonergic or dopaminergic mechanisms? Arch Gen Psychiatry 54:760. https://doi.org/10.1001/archpsyc.1997.01830200094013

    Article  CAS  PubMed  Google Scholar 

  77. Szlachta M, Kuśmider M, Pabian P et al (2018) Repeated clozapine increases the level of serotonin 5-HT1AR heterodimerization with 5-HT2A or dopamine D2 receptors in the mouse cortex. Front Mol Neurosci 11:40. https://doi.org/10.3389/fnmol.2018.00040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Funding for this study was provided by the Ontario Mental Health Foundation (Type A grant) and the Canadian Institutes of Health Research (MOP-142493 and MOP-141968). We are grateful to Wanna Mar, Research Coordinator, for providing administrative support. We also thank research volunteers Danielle Uy, Katharine Constable, Kathryn Kalahani-Bargis, and Kristy Orser for their assistance with organizing the study data for analysis.

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  1. Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health (CAMH), 250 College Street, Toronto, ON, M5T 1R8, Canada

    Parita Shah, Yusuke Iwata, Eric E. Brown, Julia Kim, Shinichiro Nakajima, Philip Gerretsen & Ariel Graff-Guerrero

  2. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Parita Shah, Eric E. Brown, Julia Kim, Margaret Hahn, Gary Remington, Philip Gerretsen & Ariel Graff-Guerrero

  3. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Yusuke Iwata, Eric E. Brown, Margaret Hahn, Gary Remington, Philip Gerretsen & Ariel Graff-Guerrero

  4. Geriatric Mental Health Division, CAMH, University of Toronto, Toronto, ON, Canada

    Eric E. Brown, Gary Remington, Philip Gerretsen & Ariel Graff-Guerrero

  5. Campbell Family Mental Health Research Institute, CAMH, University of Toronto, Toronto, ON, Canada

    Margaret Hahn, Gary Remington, Philip Gerretsen & Ariel Graff-Guerrero

  6. Krembil Centre for Neuroinformatics, CAMH, Toronto, ON, Canada

    Marcos Sanches

  7. Biostatistics Department, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

    Marcos Sanches

  8. Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada

    Margaret Hahn

  9. Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan

    Hiroyoshi Takeuchi & Shinichiro Nakajima

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  1. Parita Shah
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Correspondence to Ariel Graff-Guerrero.

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PS reports no conflict of interest. YI reports receiving fellowship grants from Keio University Medical Science Foundation, Mitsukoshi Foundation, Japan Foundation for Aging and Health, and manuscript fees from Dainippon Sumitomo Pharma. EEB reports no conflict of interest. JK and MS report no conflict of interest. HT has received speaker’s honoraria from Meiji-Seika Pharma, Mochida, Otsuka, Sumitomo Dainippon Pharma, and Yoshitomi Yakuhin and manuscript fees from Sumitomo Dainippon Pharma. SN has received fellowship grants from Canadian Institute of Health Research (CIHR), research support from Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, Daiichi Sankyo, and manuscript fees or speaker’s honoraria from Dainippon Sumitomo Pharma and Yoshitomi Yakuhin within the past three years. MH reports being on an advisory board for Alkermes in the past. GR reports external funding from CIHR, travel support from Neurocrine Biosciences, and research support from HLS. PG reports receiving research support from the CIHR, Ontario Ministry of Health and Long-Term Care, Ontario Mental Health Foundation (OMHF), and the Centre for Addiction and Mental Health (CAMH). AGG reports receiving support from the United States National Institute of Health, CIHR, OMHF, Consejo Nacional de Ciencia y Tecnología, the Instituto de Ciencia y Tecnología del DF, the Brain & Behavior Research Foundation (Formerly NARSAD), the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation Early Research Award, and Janssen.

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Shah, P., Iwata, Y., Brown, E.E. et al. Clozapine response trajectories and predictors of non-response in treatment-resistant schizophrenia: a chart review study. Eur Arch Psychiatry Clin Neurosci 270, 11–22 (2020). https://doi.org/10.1007/s00406-019-01053-6

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