Blood Cell Count Ratios at Baseline are Associated with Initial Clinical Response to Clozapine in Treatment-Resistant, Clozapine-Naïve, Schizophrenia-Spectrum Disorder

Abstract

Background Clozapine is the recommended treatment for managing treatment-resistant schizophrenia (TRS), and immunological mechanisms may be involved in its unique antipsychotic efficacy. This study investigated whether baseline immune abnormalities measured with blood cell count ratios can predict the clinical response after initiating treatment with clozapine in patients with clozapine naïve TRS.

Methods A longitudinal design was developed, involving 32 patients diagnosed with treatment-resistant, clozapine-naïve schizophrenia-spectrum disorder. Patients were evaluated at baseline before clozapine starting and 8 weeks of follow-up. Psychopathological status and immune abnormalities (blood cell count ratios: neutrophil-lymphocyte ratio [NLR], monocyte-lymphocyte ratio [MLR], platelet-lymphocyte ratio [PLR] and basophil-lymphocyte ratio [BLR]) were evaluated in each visit.

Results Baseline NLR (b=− 0.364; p=0.041) and MLR (b =− 0.400; p=0.023) predicted the change in positive symptoms over the 8-week period. Patients who exhibited a clinical response showed higher baseline NLR (2.38±0.96 vs. 1.75±0.83; p=0.040) and MLR (0.21±0.06 vs. 0.17±0.02; p=0.044) compared to non-responders. In the ROC analysis, the threshold points to distinguish between responders and non-responders were approximately 1.62 for NLR and 0.144 for MLR, yielding AUC values of 0.714 and 0.712, respectively. No statistically significant differences were observed in the blood cell count ratios from baseline to the 8-week follow-up.

Conclusion Our study emphasizes the potential clinical significance of baseline NLR and MLR levels as predictors of initial clozapine treatment response in patients with TRS. Future studies with larger sample sizes and longer follow-up periods should replicate our findings.

Keywords

treatment-resistant schizophrenia - clozapine - neutrophil-lymphocyte ratio - monocyte-lymphocyte ratio

Publikationsverlauf

Eingereicht: 18. Dezember 2023
Eingereicht: 21. Februar 2024

Angenommen nach Revision: 21. Februar 2024

Artikel online veröffentlicht:
15. April 2024

• References

• 1 Kane JM, Agid O, Baldwin ML. et al. Clinical guidance on the identification and management of treatment-resistant schizophrenia. J Clin Psychiatry 2019; 80: 2783
• 2 Samanaite R, Gillespie A, Sendt KV. et al. Biological predictors of clozapine response: A systematic review. Front Psychiatry 2018; 9: 327
• 3 Keepers GA, Fochtmann LJ, Anzia JM. et al. The American Psychiatric Association Practice Guideline for the treatment of patients with schizophrenia. Am J Psychiatry 2020; 177: 868-872
• 4 Dong S, Schneider-Thoma J, Bighelli I. et al. A network meta-analysis of efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia. Eur Arch Psychiatry Clin Neurosci
• 5 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: 772-777
• 6 Fenton C, Kang C. Clozapine is the approved option in treatment-resistant schizophrenia and requires careful management. Drugs Ther Perspect 2023; 39: 107-113
• 7 Halstead S, Siskind D, Amft M. et al. Alteration patterns of peripheral concentrations of cytokines and associated inflammatory proteins in acute and chronic stages of schizophrenia: A systematic review and network meta-analysis. Lancet Psychiatry 2023; 10: 260-271
• 8 Rømer TB, Jeppesen R, Christensen RHB. et al. Biomarkers in the cerebrospinal fluid of patients with psychotic disorders compared to healthy controls: A systematic review and meta-analysis. Mol Psychiatry 2023; 28: 2277-2290
• 9 Steen NE, Rahman Z, Szabo A. et al. Shared genetic loci between schizophrenia and white blood cell counts suggest genetically determined systemic immune abnormalities. Schizophr Bull 2023; 49: 1345-1354
• 10 Trubetskoy V, Pardiñas AF, Qi T. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature 2022; 604: 502-508
• 11 Roomruangwong C, Noto C, Kanchanatawan B. et al. The role of aberrations in the Immune-Inflammatory Response System (IRS) and the Compensatory Immune-Regulatory Reflex System (CIRS) in different phenotypes of schizophrenia: the IRS-CIRS theory of schizophrenia. Mol Neurobiol 2020; 57: 778-797
• 12 Leboyer M, Godin O, Terro E. et al. Immune signatures of treatment-resistant schizophrenia: A FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) study. Schizophr Bull Open 2021; 2: sgab012
• 13 Orbe EB, Benros ME. Immunological biomarkers as predictors of treatment response in psychotic disorders. J Pers Med 2023; 13: 1382
• 14 Jones R, Morales-Munoz I, Shields A. et al. Early neutrophil trajectory following clozapine may predict clozapine response – Results from an observational study using electronic health records. Brain Behav Immun 2023; 113: 267-274
• 15 Karageorgiou V, Milas GP, Michopoulos I. Neutrophil-to-lymphocyte ratio in schizophrenia: A systematic review and meta-analysis. Schizophr Res 2019; 206: 4-12
• 16 Mazza MG, Lucchi S, Rossetti A. et al. Neutrophil-lymphocyte ratio, monocyte-lymphocyte ratio and platelet-lymphocyte ratio in non-affective psychosis: A meta-analysis and systematic review. World J Biol Psychiatry 2020; 21: 326-338
• 17 Garcia-Rizo C, Casanovas M, Fernandez-Egea E. et al. Blood cell count in antipsychotic-naive patients with non-affective psychosis. Early Interv Psychiatry 2019; 13: 95-100
• 18 Bioque M, Matias-Martins AC, Llorca-Bofí V. et al. Neutrophil to lymphocyte ratio in patients with a first episode of psychosis: A two-year longitudinal follow-up study. Schizophr Bull 2022; 48: 1327-1335
• 19 Llorca-Bofí V, Bioque M, Font M. et al. Correlation between C-reactive protein and the inflammatory ratios in acute schizophrenia inpatients: Are they associated?. J Psychiatr Res 2023; 165: 191-196
• 20 Labonté C, Zhand N, Park A. et al. Complete blood count inflammatory markers in treatment-resistant schizophrenia: Evidence of association between treatment responsiveness and levels of inflammation. Psychiatry Res 2022; 308: 114382
• 21 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: 216-229
• 22 Garriga M, Mallorquí A, Serrano L. et al. Food craving and consumption evolution in patients starting treatment with clozapine. Psychopharmacology (Berl) 2019; 236: 3317-3327
• 23 Garriga M, Mallorquí A, Bernad S. et al. Antipsychotic-associated weight gain and clinical improvement under clozapine treatment. J Clin Psychopharmacol 2022; 42: 75-80
• 24 American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM–5). 2013
• 25 Correll CU, Agid O, Crespo-Facorro B. et al. A guideline and checklist for initiating and managing clozapine treatment in patients with treatment-resistant schizophrenia. CNS Drugs 2022; 36: 659-679
• 26 Peralta V, Cuesta MJ. Psychometric properties of the Positive and Negative Syndrome Scale (PANSS) in schizophrenia. Psychiatry Res 1994; 53: 31-40
• 27 Leucht S. Measurements of response, remission, and recovery in schizophrenia and examples for their clinical application. J Clin Psychiatry 2014; 75: 8-14
• 28 Hussain S, Ronaldson A, Arias de la Torre J. et al. Depressive and anxiety symptomatology among people with asthma or atopic dermatitis: A population-based investigation using the UK Biobank data. Brain Behav Immun 2020; 90: 138-144
• 29 Schneider A, Hommel G, Blettner M. Linear regression analysis: Part 14 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2010; 107: 776-782
• 30 Kane J, Honigfeld G, Singer J. et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-796
• 31 Leucht S, Cipriani A, Spineli L. et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet 2013; 382: 951-962
• 32 Røge R, Møller BK, Andersen CR. et al. Immunomodulatory effects of clozapine and their clinical implications: What have we learned so far?. Schizophr Res 2012; 140: 204-213
• 33 Mauri MC, Volonteri LS, Dell’Osso B. et al. Predictors of clinical outcome in schizophrenic patients responding to clozapine. J Clin Psychopharmacol 2003; 23: 660-604
• 34 Blackman G, Lisshammar JEL, Zafar R. et al. Clozapine response in schizophrenia and hematological changes. J Clin Psychopharmacol 2021; 41: 19-24
• 35 Bhikram T, Sandor P. Neutrophil-lymphocyte ratios as inflammatory biomarkers in psychiatric patients. Brain Behav Immun 2022; 105: 237-246
• 36 Jiao S, Cao T, Cai H. Peripheral biomarkers of treatment-resistant schizophrenia: Genetic, inflammation and stress perspectives. Front Pharmacol 2022; 13: 1005702
• 37 Osimo EF, Perry BI, Cardinal RN. et al. Inflammatory and cardiometabolic markers at presentation with first episode psychosis and long-term clinical outcomes: A longitudinal study using electronic health records. Brain Behav Immun 2021; 91: 117-127
• 38 Abi-Dargham A, Moeller SJ, Ali F. et al. Candidate biomarkers in psychiatric disorders: State of the field. World Psychiatry 2023; 22: 236-262