Clozapine is associated with secondary antibody deficiency

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.

Keywords: Clozapine; pneumonia; schizophrenia; secondary antibody deficiency; vaccination.

Fig. 1

Immunoglobulin levels in the clozapine-treated and clozapine-naive groups. The distribution of the serum levels of immunoglobulin (Ig)G, IgA and IgM for the clozapine-treated (light blue, n = 94) and clozapine-naive (dark blue, n = 98) groups are shown with the laboratory 5th and 95th percentile of the reference ranges for a healthy adult population represented as vertical dotted lines. The differences between the median IgG, IgA and IgM levels for the clozapine-treated versus clozapine-naive groups are all significant (P < 0.0001).

Fig. 2

Effect of duration of antipsychotic (upper) or clozapine (lower) treatment on immunoglobulin (Ig)G levels. A significant negative correlation of duration of clozapine use (years) was observed with an annual reduction in IgG levels of 0.15 g/L (P = 0.03). No correlation was seen with serum IgG level and non-clozapine antipsychotic medications (P = 0.14) despite a longer duration on therapy. Straight lines show predicted IgG at different durations of treatment (in years), based on fitted linear models. Shaded regions display pointwise 95% confidence intervals.