Skip to content
2000
image of Lurasidone vs. Other Antipsychotics as Augmentation Strategies for Clozapine in Treatment-resistant Schizophrenia: An Observational Multicenter Prospective Study

Abstract

Introduction

Clozapine, after its introduction, reshaped the landscape of Treatment-Resistant Schizophrenia (TRS) treatment, becoming the first-line treatment for that condition. However, many patients fail to respond to this drug alone. Clozapine-resistant schizophrenia (CRS) is associated with a more severe clinical presentation than TRS, manifesting in exacerbated symptoms and significantly diminished quality of life. The complex nature of CRS has prompted the development of augmentation strategies, which most commonly include another antipsychotic. The present multicenter observational study aimed to assess and compare the efficacy of Lurasidone augmentation alongside clozapine other second-generation antipsychotic combinations in patients with a schizophrenia spectrum disorder.

Methods

A total of 45 patients with a diagnosis of a schizophrenia spectrum disorder and labeled as “treatment resistant” were included. Functional and psychometric assessments were made at the baseline, one month, and six months after the treatment. A linear mixed-effect regression was performed along with other appropriate statistical analyses.

Results

A significant improvement over time was observed in the two groups for both the clinical and functional outcomes assessed, demonstrating the efficacy of a proper augmentation strategy in CRS management. Moreover, significantly lower psychiatric ward admissions were observed in the lurasidone group (.05).

Discussion

Our findings suggest that lurasidone augmentation in CRS offers significant improvements in psychopathological domains similar to alternative augmentation strategies.

Conclusion

Although further studies are needed to confirm our findings, lurasidone’s favorable side-effect profile should be considered.

Loading

Article metrics loading...

/content/journals/cn/10.2174/011570159X399781250910115949
2025-10-08
2025-10-29
Loading full text...

Full text loading...

References

  1. Howes O.D. McCutcheon R. Agid O. de Bartolomeis A. van Beveren N.J.M. Birnbaum M.L. Bloomfield M.A.P. Bressan R.A. Buchanan R.W. Carpenter W.T. Castle D.J. Citrome L. Daskalakis Z.J. Davidson M. Drake R.J. Dursun S. Ebdrup B.H. Elkis H. Falkai P. Fleischacker W.W. Gadelha A. Gaughran F. Glenthøj B.Y. Graff-Guerrero A. Hallak J.E.C. Honer W.G. Kennedy J. Kinon B.J. Lawrie S.M. Lee J. Leweke F.M. MacCabe J.H. McNabb C.B. Meltzer H. Möller H.J. Nakajima S. Pantelis C. Reis Marques T. Remington G. Rossell S.L. Russell B.R. Siu C.O. Suzuki T. Sommer I.E. Taylor D. Thomas N. Üçok A. Umbricht D. Walters J.T.R. Kane J. Correll C.U. Treatment-Resistant Schizophrenia: Treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am. J. Psychiatry 2017 174 3 216 229 10.1176/appi.ajp.2016.16050503 27919182
    [Google Scholar]
  2. Elkis H. Treatment-resistant Schizophrenia. Psychiatr. Clin. North Am. 2007 30 3 511 533 10.1016/j.psc.2007.04.001 17720034
    [Google Scholar]
  3. Kirkpatrick B. Fenton W.S. Carpenter W.T. Marder S.R. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr. Bull. 2006 32 2 214 219 10.1093/schbul/sbj053 16481659
    [Google Scholar]
  4. Demjaha A. Lappin J.M. Stahl D. Patel M.X. MacCabe J.H. Howes O.D. Heslin M. Reininghaus U.A. Donoghue K. Lomas B. Charalambides M. Onyejiaka A. Fearon P. Jones P. Doody G. Morgan C. Dazzan P. Murray R.M. Antipsychotic treatment resistance in first-episode psychosis: Prevalence, subtypes and predictors. Psychol. Med. 2017 47 11 1981 1989 10.1017/S0033291717000435 28395674
    [Google Scholar]
  5. Lally J. Ajnakina O. Di Forti M. Trotta A. Demjaha A. Kolliakou A. Mondelli V. Reis Marques T. Pariante C. Dazzan P. Shergil S.S. Howes O.D. David A.S. MacCabe J.H. Gaughran F. Murray R.M. Two distinct patterns of treatment resistance: Clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychol. Med. 2016 46 15 3231 3240 10.1017/S0033291716002014 27605254
    [Google Scholar]
  6. Meltzer H.Y. Treatment-resistant schizophrenia--the role of clozapine. Curr. Med. Res. Opin. 1997 14 1 1 20 10.1185/03007999709113338 9524789
    [Google Scholar]
  7. Prodi T. Pezzullo G. La Monica K. Priori A. Vismara M. Dell’Osso B. Benatti B. Repetitive transcranial magnetic stimulation for the treatment of depression in a real-world setting: Findings from a cohort study. Brain Sci. 2024 14 9 949 10.3390/brainsci14090949 39335443
    [Google Scholar]
  8. Iasevoli F. Giordano S. Balletta R. Latte G. Formato M.V. Prinzivalli E. De Berardis D. Tomasetti C. de Bartolomeis A. Treatment resistant Schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the most relevant predictor of poorer achievements in functional milestones. Prog. Neuropsychopharmacol. Biol. Psychiatry 2016 65 34 48 10.1016/j.pnpbp.2015.08.010 26320028
    [Google Scholar]
  9. Higashi K. Medic G. Littlewood K.J. Diez T. Granström O. De Hert M. Medication adherence in schizophrenia: Factors influencing adherence and consequences of nonadherence, a systematic literature review. Ther. Adv. Psychopharmacol. 2013 3 4 200 218 10.1177/2045125312474019 24167693
    [Google Scholar]
  10. Wong T.Y. Luo H. Tang J. Moore T.M. Gur R.C. Suen Y.N. Hui C.L.M. Lee E.H.M. Chang W.C. Yan W.C. Chui E. Poon L.T. Lo A. Cheung K.M. Kan C.K. Chen E.Y.H. Chan S.K.W. Development of an individualized risk calculator of treatment resistance in patients with first-episode psychosis (TRipCal) using automated machine learning: A 12-year follow-up study with clozapine prescription as a proxy indicator. Transl. Psychiatry 2024 14 1 50 10.1038/s41398‑024‑02754‑w 38253484
    [Google Scholar]
  11. Meltzer H.Y. Rabinowitz J. Lee M.A. Cola P.A. Ranjan R. Findling R.L. Thompson P.A. Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance. Am. J. Psychiatry 1997 154 4 475 482 10.1176/ajp.154.4.475 9090333
    [Google Scholar]
  12. Nucifora F.C. Mihaljevic M. Lee B.J. Sawa A. Clozapine as a model for antipsychotic development. Neurotherapeutics 2017 14 3 750 761 10.1007/s13311‑017‑0552‑9 28653280
    [Google Scholar]
  13. Remington G. Lee J. Agid O. Takeuchi H. Foussias G. Hahn M. Fervaha G. Burton L. Powell V. Clozapine’s critical role in treatment resistant schizophrenia: Ensuring both safety and use. Expert Opin. Drug Saf. 2016 15 9 1193 1203 10.1080/14740338.2016.1191468 27207070
    [Google Scholar]
  14. Jann M.W. Grimsley S.R. Gray E.C. Chang W.H. Pharmacokinetics and pharmacodynamics of clozapine. Clin. Pharmacokinet. 1993 24 2 161 176 10.2165/00003088‑199324020‑00005 8453823
    [Google Scholar]
  15. Luykx J.J. Gonzalez-Diaz J.M. Guu T.W. van der Horst M.Z. van Dellen E. Boks M.P. Guloksuz S. DeLisi L.E. Sommer I.E. Cummins R. Shiers D. Lee J. Every-Palmer S. Mhalla A. Chadly Z. Chan S.K.W. Cotes R.O. Takahashi S. Benros M.E. Wagner E. Correll C.U. Hasan A. Siskind D. Endres D. MacCabe J. Tiihonen J. An international research agenda for clozapine-resistant Schizophrenia. Lancet Psychiatry 2023 10 8 644 652 10.1016/S2215‑0366(23)00109‑8 37329895
    [Google Scholar]
  16. Lee J. Takeuchi H. Fervaha G. Sin G.L. Foussias G. Agid O. Farooq S. Remington G. Subtyping Schizophrenia by treatment response: Antipsychotic development and the central role of positive symptoms. Can. J. Psychiatry 2015 60 11 515 522 10.1177/070674371506001107 26720509
    [Google Scholar]
  17. Mouaffak F. Tranulis C. Gourevitch R. Poirier M.F. Douki S. Olié J.P. Lôo H. Gourion D. Augmentation strategies of clozapine with antipsychotics in the treatment of ultraresistant schizophrenia. Clin. Neuropharmacol. 2006 29 1 28 33 10.1097/00002826‑200601000‑00009 16518132
    [Google Scholar]
  18. Henna Neto J. Elkis H. Clinical aspects of super-refractory schizophrenia: A 6-month cohort observational study. Rev. Bras. Psiquiatr. 2007 29 3 228 232 10.1590/S1516‑44462007000300007 17891260
    [Google Scholar]
  19. Chakrabarti S. Clozapine resistant Schizophrenia: Newer avenues of management. World J. Psychiatry 2021 11 8 429 448 10.5498/wjp.v11.i8.429 34513606
    [Google Scholar]
  20. Wagner E. Löhrs L. Siskind D. Honer W.G. Falkai P. Hasan A. Clozapine augmentation strategies: A systematic meta-review of available evidence. Treatment options for clozapine resistance. J. Psychopharmacol. 2019 33 4 423 435 10.1177/0269881118822171 30696332
    [Google Scholar]
  21. Pai N.B. Laidlaw M. Vella S.C. Augmentation of clozapine with another pharmacological agent: Treatment for refractory schizophrenia in the ‘real world’. Acta Psychiatr. Scand. 2012 126 1 40 46 10.1111/j.1600‑0447.2012.01854.x 22432694
    [Google Scholar]
  22. Buckley P. Miller A. Olsen J. Garver D. Miller D.D. Csernansky J. When symptoms persist: Clozapine augmentation strategies. Schizophr. Bull. 2001 27 4 615 628 10.1093/oxfordjournals.schbul.a006901 11824488
    [Google Scholar]
  23. Muscatello M.R.A. Bruno A. De Fazio P. Segura-Garcia C. Pandolfo G. Zoccali R. Augmentation strategies in partial responder and/or treatment-resistant Schizophrenia patients treated with clozapine. Expert Opin. Pharmacother. 2014 15 16 2329 2345 10.1517/14656566.2014.956082 25284216
    [Google Scholar]
  24. Roerig J.L. Clozapine augmentation strategies. Ment. Health Clin. 2019 9 6 336 348 10.9740/mhc.2019.11.336 31857930
    [Google Scholar]
  25. Miyamoto S. Jarskog L.F. Fleischhacker W.W. Schizophrenia. Curr. Opin. Psychiatry 2015 28 3 243 248 10.1097/YCO.0000000000000159 25768082
    [Google Scholar]
  26. Faden J. Citrome L. Resistance is not futile: Treatment-refractory schizophrenia – overview, evaluation and treatment. Expert Opin. Pharmacother. 2019 20 1 11 24 10.1080/14656566.2018.1543409 30407873
    [Google Scholar]
  27. Yeh T.C. Correll C.U. Yang F.C. Chen M.H. Tseng P.T. Hsu C.W. Carvalho A.F. Stubbs B. Thompson T. Chu C.S. Yu C.L. Il Shin J. Yang S.N. Tu Y.K. Liang C.S. Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment. Asian J. Psychiatr. 2023 79 103375 10.1016/j.ajp.2022.103375 36470132
    [Google Scholar]
  28. Weise J. Schomerus G. Speerforck S. Add-on cariprazine in patients with long-term clozapine treatment and treatment resistant schizophrenia: Two cases of psychotic deterioration and pisa syndrome. Clin. Psychopharmacol. Neurosci. 2022 20 2 398 401 10.9758/cpn.2022.20.2.398 35466111
    [Google Scholar]
  29. Oloyede E. Clark I. Mace S. Whiskey E. Taylor D. Clozapine augmentation with cariprazine for negative symptoms: A case series and literature review. Ther. Adv. Psychopharmacol. 2022 12 20451253211066642 10.1177/20451253211066642 35111297
    [Google Scholar]
  30. Berardis D.D. Rapini G. Olivieri L. Giardini A. Lauretis I.D. Serroni N. Orsolini L. Fornaro M. Iasevoli F. Trotta S. Cottura P. Vellante F. Alessandrini M. Giannantonio M.D. Cariprazine add-on in inadequate clozapine response: A report on two cases. Clin. Psychopharmacol. Neurosci. 2021 19 1 174 178 10.9758/cpn.2021.19.1.174 33508803
    [Google Scholar]
  31. Olivola M. Arienti V. Bassetti N. Giovanna G. Brondino N. Lurasidone augmentation of clozapine in refractory schizophrenia: A case series. J. Clin. Psychopharmacol. 2023 43 2 157 160
    [Google Scholar]
  32. Cruz M.P. Lurasidone HCl (Latuda), an oral, once-daily atypical antipsychotic agent for the treatment of patients with schizophrenia. 2011 36 8 489 492 21935296
    [Google Scholar]
  33. Meyer J.M. Mao Y. Pikalov A. Cucchiaro J. Loebel A. Weight change during long-term treatment with lurasidone. Int. Clin. Psychopharmacol. 2015 30 6 342 350 10.1097/YIC.0000000000000091 26196189
    [Google Scholar]
  34. Tocco M. Newcomer J.W. Mao Y. Pikalov A. Loebel A. Lurasidone and risk for metabolic syndrome: Results from short- and long-term clinical studies in patients with schizophrenia. CNS Spectr. 2020 ••• 1 11 32921337
    [Google Scholar]
  35. Lindenmayer J.P. Czobor P. Volavka J. Citrome L. Sheitman B. McEvoy J.P. Cooper T.B. Chakos M. Lieberman J.A. Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Am. J. Psychiatry 2003 160 2 290 296 10.1176/appi.ajp.160.2.290 12562575
    [Google Scholar]
  36. Perez-Iglesias R. Crespo-Facorro B. Amado J.A. Garcia-Unzueta M.T. Ramirez-Bonilla M.L. Gonzalez-Blanch C. Martinez-Garcia O. Vazquez-Barquero J.L. A 12-week randomized clinical trial to evaluate metabolic changes in drug-naive, first-episode psychosis patients treated with haloperidol, olanzapine, or risperidone. J. Clin. Psychiatry 2007 68 11 1733 1740 10.4088/JCP.v68n1113 18052567
    [Google Scholar]
  37. Rikhari P. Kumar A. Agrawal P. Kumar H. Metabolic derangements with olanzapine and risperidone in Schizophrenia spectrum and other psychotic disorders. J. Family Med. Prim. Care 2022 11 5 2194 2200 10.4103/jfmpc.jfmpc_2161_21 35800481
    [Google Scholar]
  38. Preskorn S. Ereshefsky L. Chiu Y.Y. Poola N. Loebel A. Effect of food on the pharmacokinetics of lurasidone: results of two randomized, open‐label, crossover studies. Hum. Psychopharmacol. 2013 28 5 495 505 10.1002/hup.2338 24014143
    [Google Scholar]
  39. Meltzer H.Y. Share D.B. Jayathilake K. Salomon R.M. Lee M.A. Lurasidone improves psychopathology and cognition in treatment-resistant schizophrenia. J. Clin. Psychopharmacol. 2020 40 3 240 249 10.1097/JCP.0000000000001205 32332459
    [Google Scholar]
  40. Siwek M. Chrobak A.A. Gorostowicz A. Król P. Dudek D. Lurasidone augmentation of clozapine in Schizophrenia—retrospective chart review. Brain Sci. 2023 13 3 445 10.3390/brainsci13030445 36979255
    [Google Scholar]
  41. Nucifora F.C. Woznica E. Lee B.J. Cascella N. Sawa A. Treatment resistant Schizophrenia: Clinical, biological, and therapeutic perspectives. Neurobiol. Dis. 2019 131 104257 10.1016/j.nbd.2018.08.016 30170114
    [Google Scholar]
  42. Azur M.J. Stuart E.A. Frangakis C. Leaf P.J. Multiple imputation by chained equations: What is it and how does it work? Int. J. Methods Psychiatr. Res. 2011 20 1 40 49 10.1002/mpr.329 21499542
    [Google Scholar]
  43. Awad G. Hassan M. Loebel A. Hsu J. Pikalov A. Rajagopalan K. Health-related quality of life among patients treated with lurasidone: results from a switch trial in patients with schizophrenia. BMC Psychiatry 2014 14 1 53 10.1186/1471‑244X‑14‑53 24559217
    [Google Scholar]
  44. Awad G. Ng-Mak D. Rajagopalan K. Hsu J. Pikalov A. Loebel A. Long-term health-related quality of life improvements among patients treated with lurasidone: Results from the open-label extension of a switch trial in Schizophrenia. BMC Psychiatry 2016 16 1 176 10.1186/s12888‑016‑0879‑5 27245981
    [Google Scholar]
  45. Li X. Frye M.A. Shelton R.C. Clozapine augmentation in treatment-resistant Schizophrenia: A systematic review and meta-analysis. Am. J. Psychiatry 2021 178 6 525 538
    [Google Scholar]
  46. Dold M. Leucht S. Pharmacotherapy of treatment-resistant Schizophrenia: A clinical perspective. Evid. Based Ment. Health 2016 19 4 147 153 24713315
    [Google Scholar]
  47. Meyer J.M. Loebel A. Schweizer E. Lurasidone: A comprehensive review of its clinical profile and putative mechanism of action. CNS Spectr. 2020 25 5 508 521
    [Google Scholar]
  48. Meltzer H.Y. Bobo W.V. Augmentation of clozapine with antipsychotics for treatment-resistant schizophrenia: A concise review. CNS Drugs 2020 34 7 737 749
    [Google Scholar]
  49. De Berardis D. Rapini G. Olivieri L. Safety, efficacy, and tolerability of Lurasidone in schizophrenia: A critical review. Drug Des. Devel. Ther. 2018 12 1657 1673
    [Google Scholar]
  50. Srisurapanont M. Suttajit S. Likhitsathian S. Maneeton B. Maneeton N. A network meta-analysis of the dose-response effects of lurasidone on acute Schizophrenia. Sci. Rep. 2021 11 1 5571 10.1038/s41598‑021‑84836‑z 33692392
    [Google Scholar]
/content/journals/cn/10.2174/011570159X399781250910115949
Loading
/content/journals/cn/10.2174/011570159X399781250910115949
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test