Background: Clozapine is the only licensed pharmacotherapy for patients with treatment-resistant schizophrenia (TRS), but its use is limited due to adverse effects. Clozapine treatment has been recently associated with reductions in immunoglobulin (Ig) levels cross-sectionally, however prospective studies are required to establish longitudinal effects. This study aimed to determine whether reductions in immunoglobulin levels occur over 6 months after initiating clozapine treatment. An exploratory aim was to investigate relationships between immunoglobulin levels and symptom severity over the course of clozapine treatment. Methods: In 56 participants with TRS, Ig A, M and G levels were measured in serum using a sandwich immunoassay. Samples for analysis were acquired prior to starting clozapine and at 6, 12 and 24 weeks after initiating clozapine treatment. Clinical symptoms were measured using the positive and negative syndrome scale for schizophrenia (PANSS). Results: All three classes of Ig decreased during clozapine treatment. For IgA and IgG the reduction was significant at 24 weeks (IgA: B - 32.7, 95% CI = -61.19, -4.2, p = 0.04; IgG: B - 55.94, 95% CI = -111.03, -0.844, p = 0.05). For IgM the reduction was significant at 12 and 24 weeks (12 weeks: B = -21.73, 95% CI = -37.10, -6.35, p = 0.006; 24 weeks: B = -32.54, 95% CI = -48.89, 16.18, p = 0.0001). Changes in both IgA and IgG were correlated with the percentage change in PANSS total scores over 12 weeks, such that greater reductions in IgA and IgG during clozapine treatment were associated with greater reductions in symptom severity (n = 32, IgA r = 0.59, p = 0.005; IgG r = 0.50, p = 0.02) Conclusions: The observed reductions in immunoglobulin levels over six months of clozapine treatment add further evidence linking clozapine to secondary antibody deficiency. The associations between Ig reduction and symptom improvement may however indicate that immune mechanisms contribute to both desirable and undesirable effects of clozapine.

The authors have declared no competing interest.

This work was funded by a grant to DC and JHM from the European Union FP-7 programme, CRESTAR, grant reference 13/LO/1857, and a grant to AE from the Medical Research Council, UK, Grant MR/L003988/1. This study presents independent research funded in part by the National Institute for Health Research (NIHR), Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King's College London.

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Ethics committee of London South East NHS gave ethical approval for this work (Ref:13/LO/1857)

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