Clozapine-associated secondary antibody deficiency

Abstract

Purpose of review: Clozapine has recently been described as a novel cause of secondary antibody deficiency (SAD), associated with long-term therapy. Here we critically review the evidence linking clozapine-use to an increased infection risk, describe immunological alterations, and discuss potential mechanisms. Findings: Individuals with schizophrenia are at 2-5 times more likely to develop pneumonia than the general population, in particular when receiving clozapine. Delayed-onset distinguishes clozapineassociated hypogammaglobulinaemia from agranulocytosis or neutropenia that occur at lesser frequency. Biomarker searches in treatment-resistant schizophrenia highlight an immune signature associated with long-term clozapine use. This includes reduction in class-switched memory B-cells, echoing common variable immunodeficiency. Recent identification of a role for dopamine in T follicular helper-B cell interactions may inform future clinical studies. Summary: The detrimental impact of the increased infection risk associated with clozapine necessitates a re-evaluation of the current monitoring strategies as well as further studies to better understand the underlying mechanisms of SAD in this setting. Based on available evidence, we suggest simple modifications to clozapine monitoring including integration of routine vaccination, smoking cessation, and assessment of humoral immunity. Further studies are required to understand the role of clozapine in neuroinflammation as well as potentially other autoantibody mediated diseases.

Management of clozapine treatment during the COVID-19 pandemic

“…41 Reductions in pneumococcal-specific IgA and IgM were also observed. 43 A longer duration of clozapine use was associated with a higher risk of hypogammaglobulinaemia (annual decline of 0.15 g/l). 42 The magnitude of the reduction was larger than that caused by rituxumab and methotrexate immunosuppressant therapy in rheumatoid arthritis.…”

“…Early recent research from one research group has found a reduction in immunoglobulin levels in patients taking clozapine, with a greater effect in those taking long-term treatment. 41–43 These studies found clinically significant panhypogammaglobulinaemia and impaired vaccine responses in patients taking clozapine that were not fully explained by smoking or concurrent medication. 41 Reductions in pneumococcal-specific IgA and IgM were also observed.…”

COVID-19 vaccination for people with severe mental illness: why, what, and how?

“…A secondary antibody deficiency has been observed in patients with long-term clozapine use, putting these patients at risk of immunodeficiency. 79 In a retrospective cohort study, clozapine was a possible risk factor for SARS-CoV-2 infection. 80 Although a small study showed that influenza vaccination had no effect on clozapine serum concentrations, 81 vaccination might affect clozapine concentrations through its action on cytochrome P450 metabolism.…”

COVID-19 infection causes a reduction in neutrophil counts in patients taking clozapine

“…The propensity of clozapine to cause adverse effects such as weight gain may also increase the risk of infection, and there is emerging evidence of a direct effect of clozapine on immunoglobulins. 5 These factors, including the reduction in immunoglobulins, has led to fears that patients taking clozapine might be particularly vulnerable to coronavirus infection. Data have recently been published that confirm these concerns, dem-onstrating that patients taking clozapine are indeed at increased risk for COVID-19.…”