Original Research Focus on Psychosis May 1, 2024

Beneficial Effects of Concomitant Long-Acting Injectable Antipsychotics on Time to Rehospitalization in Patients With Treatment-Resistant Schizophrenia Receiving Clozapine: A Retrospective Cohort Study

Yun Tien, MD; Xi-Yu Wang, MD; Shang-Chien Huang, MD; Hsiang-Ping Huang, PhD

J Clin Psychiatry 2024;85(2):23m15071

Abstract

Introduction: This study aimed to assess the association between long-acting injectable (LAI) antipsychotic prescription and the risk of psychiatric hospitalization in patients with treatment-resistant schizophrenia (TRS) receiving clozapine.

Methods: In this retrospective cohort study at a single tertiary psychiatric center, we analyzed rehospitalization hazard ratios (HRs) in refractory schizophrenia patients, classified by DSM-IV-TR and DSM-5 criteria. We examined various psychotropic regimens—clozapine with or without other oral antipsychotics (OAPs) or LAI antipsychotics. Subgroups were stratified by daily clozapine dosage and previous admissions.

Results: A total of 719 patients were included in the study. Analyses were conducted on all the patients over 3- month, 6-month, and 1-year periods. Patients treated with a combination of clozapine and LAI antipsychotics (CLO + LAI) had a significantly higher number of previous hospitalizations (P = .003), and a higher daily dose of clozapine (P < .001) was found in the CLO + OAP group than in the CLO (monotherapy) group and the CLO + LAI group. Patients treated with LAI antipsychotic comedication had significantly lower HRs for rehospitalization in 1 year among 3 studied groups. Moreover, the protective effects of LAI antipsychotics were observed in all the subgroups stratified by daily clozapine dosage and number of previous admissions to represent disease severity.

Conclusion: The combination of clozapine and LAI antipsychotics was associated with a significantly lower risk of rehospitalization compared to both the combination of clozapine and OAPs and clozapine monotherapy. The use of LAI antipsychotics should be considered to prevent rehospitalization in patients with TRS who are already being treated with clozapine.

J Clin Psychiatry 2024;85(2):23m15071

Author affiliations are listed at the end of this article.

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  1. Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 2015;1:15067. PubMed CrossRef
  2. Ceraso A, Lin JJ, Schneider-Thoma J, et al. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev. 2020;8(8):Cd008016. PubMed CrossRef
  3. Lally J, Gaughran F, Timms P, et al. Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics. Pharmgenomics Pers Med. 2016;9:117–129. PubMed CrossRef
  4. Iasevoli F, Giordano S, Balletta R, et al. 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. PubMed CrossRef
  5. Galderisi S, Rossi A, Rocca P, et al. The influence of illness-related variables, personal resources and context-related factors on real-life functioning of people with schizophrenia. World Psychiatry. 2014;13(3):275–287. PubMed CrossRef
  6. Bighelli I, Rodolico A, García-Mieres H, et al. Psychosocial and psychological interventions for relapse prevention in schizophrenia: a systematic review and network meta-analysis. Lancet Psychiatry. 2021;8(11):969–980. PubMed CrossRef
  7. Valenstein M, Ganoczy D, McCarthy JF, et al. Antipsychotic adherence over time among patients receiving treatment for schizophrenia: a retrospective review. J Clin Psychiatry. 2006;67(10):1542–1550. PubMed CrossRef
  8. Olivares JM, Sermon J, Hemels M, et al. Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review. Ann Gen Psychiatry. 2013;12(1):32. PubMed CrossRef
  9. Lieberman JA, Safferman AZ, Pollack S, et al. Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry. 1994;151(12):1744–1752. PubMed CrossRef
  10. Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta analysis. Can J Psychiatry. 2017;62(11):772–777. PubMed CrossRef
  11. Nucifora FC Jr, Mihaljevic M, Lee BJ, et al. Clozapine as a model for antipsychotic development. Neurotherapeutics. 2017;14(3):750–761. PubMed CrossRef
  12. Miller DD. Review and management of clozapine side effects. J Clin Psychiatry. 2000;61(suppl 8):14–17. PubMed
  13. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–951. PubMed CrossRef
  14. Lally J, Tully J, Robertson D, et al. Augmentation of clozapine with electroconvulsive therapy in treatment resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2016;171(1–3):215–224. PubMed CrossRef
  15. Lally J, Breese E, Osman M, et al. Augmentation of clozapine with ECT: a retrospective case analysis. Acta Neuropsychiatr. 2021;33(1):31–36. CrossRef
  16. Barber S, Olotu U, Corsi M, et al. Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2017;3(3):Cd006324. PubMed CrossRef
  17. Repo-Tiihonen E, Hallikainen T, Kivistö P, et al. Antipsychotic polypharmacy in clozapine resistant schizophrenia: a randomized controlled trial of tapering antipsychotic Co-treatment. Ment Illn. 2012;4(1):e1. PubMed CrossRef
  18. Caliskan AM, Karaaslan M, Inanli I, et al. The effects of adding long-acting injectable antipsychotic drugs to clozapine on relapse and hospitalization in patients with treatment-resistant schizophrenia: a mirror-image retrospective study. Int Clin Psychopharmacol. 2021;36(1):30–33. PubMed CrossRef
  19. Sepede G, Di Iorio G, Spano MC, et al. A case of resistant schizophrenia successfully treated with clozapine/long-acting injectable aripiprazole combination. Clin Neuropharmacol. 2016;39(6):322–324. PubMed CrossRef
  20. Kennedy JL, Altar CA, Taylor DL, et al. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol. 2014;29(2):63–76. PubMed CrossRef
  21. Meltzer HY, Lindenmayer JP, Kwentus J, et al. A six month randomized controlled trial of long acting injectable risperidone 50 and 100mg in treatment resistant schizophrenia. Schizophr Res. 2014;154(1–3):14–22. PubMed CrossRef
  22. Kimura H, Kanahara N, Komatsu N, et al. A prospective comparative study of risperidone long-acting injectable for treatment-resistant schizophrenia with dopamine supersensitivity psychosis. Schizophr Res. 2014;155(1–3):52–58. PubMed CrossRef
  23. Kimura H, Kanahara N, Sasaki T, et al. Risperidone long-acting injectable in the treatment of treatment-resistant schizophrenia with dopamine supersensitivity psychosis: results of a 2-year prospective study, including an additional 1-year follow-up. J Psychopharmacol. 2016;30(8):795–802. PubMed CrossRef
  24. Bioque M, Parellada E, García-Rizo C, et al. Clozapine and paliperidone palmitate antipsychotic combination in treatment-resistant schizophrenia and other psychotic disorders: a retrospective 6-month mirror-image study. Eur Psychiatry. 2020;63(1):e71. PubMed CrossRef
  25. Souaiby L, Gauthier C, Rieu C, et al. Clozapine and long-acting injectable antipsychotic combination: a retrospective one-year mirror-image study. Schizophr Res. 2017;188:89–91. PubMed CrossRef
  26. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision (DSM-IV-TR). American Psychiatric Association; 2000.
  27. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013;21:591–643.
  28. Dixon L. Dual diagnosis of substance abuse in schizophrenia: prevalence and impact on outcomes. Schizophr Res. 1999;35(suppl):S93–100. PubMed CrossRef
  29. Yücel M, Bora E, Lubman DI, et al. The impact of cannabis use on cognitive functioning in patients with schizophrenia: a meta-analysis of existing findings and new data in a first-episode sample. Schizophr Bull. 2012;38(2):316–330.
  30. Gardner DM, Murphy AL, O’Donnell H, et al. International consensus study of antipsychotic dosing. Am J Psychiatry. 2010;167(6):686–693. PubMed CrossRef
  31. Howes OD, McCutcheon R, Agid O, et al. 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. PubMed CrossRef
  32. Wagner E, Kane JM, Correll CU, et al. Clozapine combination and augmentation strategies in patients with schizophrenia—recommendations from an international expert survey among the Treatment Response and Resistance in Psychosis (TRRIP) working group. Schizophr Bull. 2020;46(6):1459–1470. PubMed CrossRef
  33. Li YY, Zhang YS, Wang J, et al. Optimal treatment strategies of clozapine for refractory schizophrenia. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2016;38(6):666–678. PubMed CrossRef
  34. Siskind DJ, Lee M, Ravindran A, et al. Augmentation strategies for clozapine refractory schizophrenia: a systematic review and meta-analysis. Aust N Z J Psychiatry. 2018;52(8):751–767. PubMed CrossRef
  35. Foster R, Olajide D. A case of clozapine-induced tonic-clonic seizures managed with valproate: implications for clinical care. J Psychopharmacol. 2005;19(1):93–96. PubMed CrossRef
  36. Guha P, Nizamie HS. Refractory schizophrenia, clozapine and epilepsy: management strategies. Indian J Psychiatry. 1998;40(1):84–86. PubMed
  37. Jahołkowski P, Niewiadomska J, Wciórka J, et al. Clozapine-induced myocarditis during co-administration of valproate: a case report. Psychiatr Pol. 2019;53(5):997–1002.
  38. Malik S, Lally J, Ajnakina O, et al. Sodium valproate and clozapine induced neutropenia: a case control study using register data. Schizophr Res. 2018;195:267–273. PubMed CrossRef
  39. Jakobsen MI, Grønborg H, Hansen HV, et al. Clozapine-associated neutropenia following augmentation with sodium valproate. SAGE Open Med Case Rep. 2021;9:2050313X211019791. PubMed CrossRef
  40. Correll CU, Gallego JA. Antipsychotic polypharmacy: a comprehensive evaluation of relevant correlates of a long-standing clinical practice. Psychiatr Clin North Am. 2012;35(3):661–681. PubMed CrossRef
  41. Lauriello J, Weiden PJ, Gleeson CD, et al. Real-world outcomes and costs following 6 months of treatment with the long-acting injectable (LAI) aripiprazole lauroxil for the treatment of schizophrenia. CNS Drugs. 2021;35(10):1123–1135. CrossRef
  42. Marcus SC, Zummo J, Pettit AR, et al. Antipsychotic adherence and rehospitalization in schizophrenia patients receiving oral versus long-acting injectable antipsychotics following hospital discharge. J Manag Care Spec Pharm. 2015;21(9):754–768. CrossRef
  43. Taipale H, Mehtälä J, Tanskanen A, et al. Comparative effectiveness of antipsychotic drugs for rehospitalization in schizophrenia—a nationwide study with 20-year follow-up. Schizophr Bull. 2018;44(6):1381–1387. PubMed CrossRef
  44. Lin CH, Chen FC, Chan HY, et al. A comparison of long-acting injectable antipsychotics with oral antipsychotics on time to rehospitalization within 1 year of discharge in elderly patients with schizophrenia. Am J Geriatr Psychiatry. 2020;28(1):23–30. CrossRef
  45. Rubio JM, Schoretsanitis G, John M, et al. Psychosis relapse during treatment with long-acting injectable antipsychotics in individuals with schizophrenia spectrum disorders: an individual participant data meta-analysis. Lancet Psychiatry. 2020;7(9):749–761. PubMed CrossRef
  46. Lauriello J. Prevalence and impact of relapse in patients with schizophrenia. J Clin Psychiatry. 2020;81(2):MS19053BR1C. PubMed CrossRef
  47. Abdel-Baki A, Medrano S, Maranda C, et al. Impact of early use of long acting injectable antipsychotics on psychotic relapses and hospitalizations in first-episode psychosis. Int Clin Psychopharmacol. 2020;35(4):221–228. PubMed CrossRef
  48. Salgueiro M, Segarra R. Long-acting injectable second-generation antipsychotics in first-episode psychosis: a narrative review. Int Clin Psychopharmacol. 2019;34(2):51–56. PubMed CrossRef
  49. Seok Jeong B, Kwon JS, Yoon Kim S, et al. Functional imaging evidence of the relationship between recurrent psychotic episodes and neurodegenerative course in schizophrenia. Psychiatry Res. 2005;139(3):219–228. PubMed CrossRef
  50. Emsley R, Chiliza B, Asmal L, et al. The nature of relapse in schizophrenia. BMC Psychiatry. 2013;13:50. PubMed CrossRef