Exposing the link between clozapine, infection and antibody deficiency

Dr Mark Ponsford and Cara Jenkins of the SIROC team.

The possibility of a link between antibody deficiency and clozapine use was first raised through the introduction of calculated globulin screening in Wales by Professor Stephen Jolles.¹ Calculated globulin is derived from the difference between total serum protein and albumin concentrations. Because immunoglobulins form a significant proportion of this globulin fraction, a low calculated globulin value may suggest antibody deficiency. Calculated globulin is included in liver function testing throughout Wales, and with over three million tests performed each year, this offers a screening tool to help trigger recognition of antibody deficiency. During our initial evaluation of calculated globulin screening, clozapine use was recorded in 13% of cases where marked reduction of serum IgG antibody levels were identified.¹

We conducted a pilot study to explore this,² inviting approximately 200 adults with schizophrenia-like illness attending community mental health clinics around Cardiff to donate blood and allow us to review their medical history.² We found immunoglobulins were all significantly reduced in the clozapine-treated group, compared with clozapine-naive individuals receiving an alternate antipsychotic.

Despite reporting our findings to the UK Medicines and Healthcare Regulatory Authority (MHRA), antibody deficiency is not a listed side effect of clozapine in the British National Formulary.³ It is possible that limitations of our pilot study, such as sample size and single health board may limit its generalisability. We therefore sought to extend and validate these findings. Thanks to funding support from Health & Care Research Wales we have recently completed a wider study – The Secure Anonymised Information Linkage (SAIL) databank analysis of Infection Related Outcomes in people with schizophrenia taking Clozapine (SIROC).

Here, Dr Mark Ponsford, the SIROC principal investigator discusses the key questions posed, and how the team have addressed them.

Are respiratory tract infections more common in individuals receiving clozapine?

We were extremely fortunate to access the SAIL Databank, a unique resource which holds anonymised healthcare data from patients from across Wales. Working with Professor Ann John and the SAIL team, we were able to examine records of antibiotic prescribing and clinical diagnoses of infection made by general practitioners for individuals with schizophrenia-like illness prescribed clozapine or an alternate antipsychotic therapy in almost 43,000 patients across Wales. This gives us tremendous power to look for differences in infection rates.

Is antibody deficiency more common in individuals receiving clozapine therapy?

We really wanted to involve people with serious mental illness from across Wales to take part in this research. We were delighted that almost 300 participants agreed to take part and donated blood. We were grateful for input from a participant in our pilot study, who flagged that using leftover samples could really help us boost engagement.

Is there a link between antibody levels and infections in individuals with schizophrenia?

Here our team carefully examined each participant’s infection history, antibiotic use and antibody levels. We have also worked with immunology colleagues across the UK to gauge their experience of dealing with clozapine-associated antibody deficiency to address this.

What does the SIROC study show?

Our analysis is ongoing, but there is strong evidence of a heightened infection risk associated with clozapine therapy. The odds of finding a low antibody (immunoglobulin G) level was over six-times more likely in those prescribed clozapine, compared with an alternative antipsychotic. It’s also clear that clozapine-associated antibody deficiency exists outside of Wales, and that specialist immunology input can be helpful in management.

What impact would diagnosis of antibody deficiency have on an individual’s care?

The study team have worked closely with the Immunodeficiency Centre for Wales’s patient representative group, including Group co-chair Cara Jenkins, 42, from Cardiff, who was diagnosed with a type of immunodeficiency called Common Variable Immunodeficiency (CVID) in 2011. Cara said, “Immunodeficiency is an invisible condition, which makes it so difficult to identify. Before I was diagnosed, I was so unwell with repeated infections. It was almost constant. Once I started treatment my quality of life just transformed. Thankfully my condition was caught before I developed lung damage which many immunodeficient patients develop.”

“There are so many people in Wales yet to be diagnosed with antibody deficiency, including people with schizophrenia who are taking this medication, who would benefit from life-changing antibody treatment but they just don’t know yet.” Cara, who also has previous experience of taking antipsychotic medication, is passionate about the importance of research in progressing treatment for immunodeficiency and mental illness. She continued, “It means a lot to be involved in this research, to further knowledge of a condition people may have less awareness of, and which joins up mental and physical health. Having seen the benefits of immunotherapy myself, I really believe it could transform patients’ lives in the future.”

Three graphs showing the reduction across immunoglobulin classes with clozapine therapy

Should patients taking clozapine be worried?

Co-investigators Professor James Walters (Lead for the National Centre for Mental Health) and Tayeeb Tahir (consultant psychiatrist) are quick to reassure that “Clozapine remains one of the most effective medications for schizophrenia and saves lives. This study identifies an important area that may help further improve patient safety for those who need this essential medication.”

What are the likely next steps?

At present, we can only speculate regarding the potential mechanism contributing (discussed in Ponsford et al).⁴ Perhaps this isn’t entirely surprising as the exact mechanisms that make clozapine such an effective antipsychotic remain unknown – even through it was first licensed in the UK in 1990.

This work adds to the mounting evidence of the vulnerability of individuals with severe mental illness to infection. Although antibody deficiency remains uncommon, patients taking clozapine already have regular blood tests, making it relatively simple to introduce additional screening of samples to monitor antibody levels. Remarkably to us, despite extensive and regular blood testing, antibody deficiency isn’t considered at present.

References

Jolles et al. 2014 Calculated globulin (CG) as a screening test for antibody deficiency. Clin Exp Immunol. 177 671–678.
Ponsford et al. 2018 Clozapine is associated with secondary antibody deficiency. Br J Psychiatry. 214 1–7.
Ponsford & Jolles. 2019 Antibody deficiency in patients taking clozapine. BMJ. 364. Available from: https://www.bmj.com/content/364/bmj.l483
Ponsford et al. 2019 Clozapine-associated secondary antibody deficiency. Curr Opin Allergy Clin Immunol. 19 553–562.