Skip to main content
×
×
Home

Clozapine is associated with secondary antibody deficiency

  • Mark Ponsford (a1), Daniel Castle (a2), Tayyeb Tahir (a3), Rebecca Robinson (a4), Wendy Wade (a5), Rachael Steven (a6), Kathryn Bramhall (a7), Mo Moody (a7), Emily Carne (a8), Catherine Ford (a9), Daniel Farewell (a10), Paul Williams (a11), Tariq El-Shanawany (a11) and Stephen Jolles (a12)...
Abstract
Background

Schizophrenia affects 1% of the population. Clozapine is the only medication licensed for treatment-resistant schizophrenia and is intensively monitored to prevent harm from neutropenia. Clozapine is also associated with increased risk of pneumonia although the mechanism is poorly understood.

Aims

To investigate the potential association between clozapine and antibody deficiency.

Methods

Patients taking clozapine and patients who were clozapine-naive and receiving alternative antipsychotics were recruited and completed a lifestyle, medication and infection-burden questionnaire. Serum total immunoglobulins (immunoglobulin (Ig)G, IgA, IgM) and specific IgG antibodies to haemophilus influenzae type B, tetanus and IgG, IgA and IgM to pneumococcus were measured.

Results

Immunoglobulins were all significantly reduced in the clozapine-treated group (n = 123) compared with the clozapine-naive group (n = 111). Odds ratios (ORs) for a reduction in clozapine:control immunoglobulin values below the fifth percentile were IgG, OR = 6.00 (95% CI 1.31–27.44); IgA, OR = 16.75 (95% CI 2.18–128.60); and IgM, OR = 3.26 (95% CI 1.75–6.08). These findings remained significant despite exclusion of other potential causes of hypogammaglobulinaemia. In addition, duration on clozapine was associated with decline in IgG. A higher proportion of the clozapine-treated group reported taking more than five courses of antibiotics in the preceding year (5.3% (n = 5) versus 1% (n = 1).

Conclusions

Clozapine use was associated with significantly reduced immunoglobulin levels and an increased proportion of patients using more than five antibiotic courses in a year. Antibody testing is not included in existing clozapine monitoring programmes but may represent a mechanistic explanation and modifiable risk factor for the increased rates of pneumonia and sepsis-related mortality previously reported in this vulnerable cohort.

Declaration of interest

S.J. has received support from CSL Behring, Shire, LFB, Biotest, Binding Site, Sanofi, GSK, UCB Pharma, Grifols, BPL SOBI, Weatherden, Zarodex and Octapharma for projects, advisory boards, meetings, studies, speaker and clinical trials.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Clozapine is associated with secondary antibody deficiency
      Available formats
      ×
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Clozapine is associated with secondary antibody deficiency
      Available formats
      ×
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Clozapine is associated with secondary antibody deficiency
      Available formats
      ×
Copyright
This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike licence (http://creativecommons.org/licenses/by-nc-nd-sa/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the same Creative Commons licence is included and the original work is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use.
Corresponding author
Correspondence: Stephen Jolles, Immunodeficiency Centre for Wales, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK. Email: jollessr@cardiff.ac.uk
References
Hide All
1Owen, MJ, Sawa, A, Mortensen, PB. Schizophrenia. Lancet 2016; 388: 8697.
2Hor, K, Taylor, M. Suicide and schizophrenia: a systematic review of rates and risk factors. J Psychopharmacol 2010; 24 (4 suppl): 8190.
3Tiihonen, J, Lonnqvist, J, Wahlbeck, K, Klaukka, T, Niskanen, L, Tanskanen, A, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009; 374: 620–7.
4Copeland, LA, Mortensen, EM, Zeber, JE, Pugh, MJ, Restrepo, MI, Dalack, GW. Pulmonary disease among inpatient decedents: impact of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 720–6.
5Walker, AM, Lanza, LL, Arellano, F, Rothman, KJ. Mortality in current and former users of clozapine. Epidemiology 1997; 8: 671–7.
6Hung, GC, Liu, HC, Yang, SY, Pan, CH, Liao, YT, Chen, CC, et al. Antipsychotic reexposure and recurrent pneumonia in schizophrenia: a nested case-control study. J Clin Psychiatry 2016; 77: 60–6.
7Leung, JG, Hasassri, ME, Barreto, JN, Nelson, S, Morgan, RJ 3rd. Characterization of admission types in medically hospitalized patients prescribed clozapine. Psychosomatics 2017; 58: 164–72.
8Stoecker, ZR, George, WT, O'Brien, JB, Jancik, J, Colon, E, Rasimas, JJ. Clozapine usage increases the incidence of pneumonia compared with risperidone and the general population: a retrospective comparison of clozapine, risperidone, and the general population in a single hospital over 25 months. Int Clin Psychopharmacol 2017; 32: 155–60.
9Kuo, CJ, Yang, SY, Liao, YT, Chen, WJ, Lee, WC, Shau, WY, et al. Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophr Bull 2013; 39: 648–57.
10Mustafa, FA, Burke, JG, Abukmeil, SS, Scanlon, JJ, Cox, M. ‘Schizophrenia past clozapine’: reasons for clozapine discontinuation, mortality, and alternative antipsychotic prescribing. Pharmacopsychiatry 2015; 48: 11–4.
11Taylor, DM, Douglas-Hall, P, Olofinjana, B, Whiskey, E, Thomas, A. Reasons for discontinuing clozapine: matched, case-control comparison with risperidone long-acting injection. Br J Psychiatry 2009; 194: 165–7.
12Abdelmawla, N, Ahmed, MI. Clozapine and risk of pneumonia. Br J Psychiatry 2009; 194: 468–9.
13Bello, S, Menendez, R, Torres, A, Reyes, S, Zalacain, R, Capelastegui, A, et al. Tobacco smoking increases the risk for death from pneumococcal pneumonia. Chest 2014; 146: 1029–37.
14Jolles, S, Borrell, R, Zouwail, S, Heaps, A, Sharp, H, Moody, M, et al. Calculated globulin (CG) as a screening test for antibody deficiency. Clin Exp Immunol 2014; 177: 671–8.
15Jolles, S. The variable in common variable immunodeficiency: a disease of complex phenotypes. J. Allergy Clin Immunol Pract 2013; 1: 545–56.
16Milford, W. A., Joanna, S., Rowbottom, A, Wild, GD. Handbook of Clinical Immunochemistry (9th edn). PRU Publications, 2007.
17European Society of Immunodeficiences. Diagnostic Criteria for Primary Immunodeficiency. ESID, no date (https://esid.org/Working-Parties/Clinical/Resources/Diagnostic-criteria-for-PID2#Q6).
18Chua, I, Lagos, M, Charalambous, BM, Workman, S, Chee, R, Grimbacher, B. Pathogen-specific IgG antibody levels in immunodeficient patients receiving immunoglobulin replacement do not provide additional benefit to therapeutic management over total serum IgG. J Allergy Clin Immunol 2011; 127: 1410–1.
19Meltzer, HY, Alphs, L, Green, AI, Altamura, AC, Anand, R, Bertoldi, A, et al. Clozapine treatment for suicidality in schizophrenia: international Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003; 60: 8291.
20National Institute for Health and Care Excellence. Psychosis and Schizophrenia in Adults: Prevention and Management.NICE, 2014.
21van Vollenhoven, RF, Emery, P, Bingham, CO 3rd, Keystone, EC, Fleischmann, RM, Furst, DE, et al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 2013; 72: 1496–502.
22Christou, EAA, Giardino, G, Worth, A, Ladomenou, F. Risk factors predisposing to the development of hypogammaglobulinemia and infections post-Rituximab. Int Rev Immunol 2017; 36: 352–9.
23Resnick, ES, Moshier, EL, Godbold, JH, Cunningham-Rundles, C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 2012; 119: 1650–7.
24McMillan, SA, Douglas, JP, Archbold, GP, McCrum, EE, Evans, AE. Effect of low to moderate levels of smoking and alcohol consumption on serum immunoglobulin concentrations. J Clin Pathol 1997; 50: 819–22.
25Kelly, C, McCreadie, RG. Smoking habits, current symptoms, and premorbid characteristics of schizophrenic patients in Nithsdale, Scotland. Am J Psychiatry 1999; 156: 1751–7.
26Roge, R, Moller, BK, Andersen, CR, Correll, CU, Nielsen, J. Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far? Schizophr Res 2012; 140: 204–13.
27Alvir, JM, Lieberman, JA, Safferman, AZ, Schwimmer, JL, Schaaf, JA. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med 1993; 329: 162–7.
28Lozano, R, Marin, R, Santacruz, MJ, Pascual, A. Selective immunoglobulin M deficiency among clozapine-treated patients: a nested case-control study. Prim Care Companion CNS Disord 2015; 17: 10.4088/PCC.
29Jolles, S, Chapel, H, Litzman, J. When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency - a practical approach. Clin Exp Immunol 2016; 188: 333–41.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
  • URL: /core/journals/the-british-journal-of-psychiatry
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Type Description Title
WORD
Supplementary materials

Ponsford et al. supplementary material
Ponsford et al. supplementary material 1

 Word (720 KB)
720 KB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 19
Total number of PDF views: 318 *
Loading metrics...

Abstract views

Total abstract views: 428 *
Loading metrics...

* Views captured on Cambridge Core between 12th September 2018 - 19th September 2018. This data will be updated every 24 hours.

Clozapine is associated with secondary antibody deficiency

  • Mark Ponsford (a1), Daniel Castle (a2), Tayyeb Tahir (a3), Rebecca Robinson (a4), Wendy Wade (a5), Rachael Steven (a6), Kathryn Bramhall (a7), Mo Moody (a7), Emily Carne (a8), Catherine Ford (a9), Daniel Farewell (a10), Paul Williams (a11), Tariq El-Shanawany (a11) and Stephen Jolles (a12)...
Submit a response

eLetters

No eLetters have been published for this article.

×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *