First case series of clozapine induced hypogammaglobulinaemia in England

Schizophrenia is a debilitating psychiatric condition and clozapine is recommended for patients who are unresponsive to, or intolerant of, conventional antipsychotic drugs [1]. Clozapine has numerous possible side-effects,1 among which neutropenia and fatal agranulocytosis are well-documented [2]. More recently, an association between clozapine treatment and hypogammaglobulinaemia has been reported [3].


Introduction
Schizophrenia is a debilitating psychiatric condition and clozapine is recommended for patients who are unresponsive to, or intolerant of, conventional antipsychotic drugs [1]. Clozapine has numerous possible side-effects, 1 among which neutropenia and fatal agranulocytosis are well-documented [2].
More recently, an association between clozapine treatment and hypogammaglobulinaemia has been reported [3].
Among four clinical immunology centres in the north west of England, we identifi ed 17 clozapine-treated patients who were referred with hypogammaglobulinaemia for which there was no other likely cause. We describe the clinical and immunological phenotypes of these patients, and their management.
Additionally, we speculate that a possible mechanism for this drug side-effect is interaction with PI3 kinase pathways involved in the development and maturation of B cells.

Aim
To review the diagnosis and management of hypogammaglobulinaemia in patients on long-term clozapine treatment.

Method
Retrospective review of medical notes and electronic patient records was undertaken to obtain information on the following:

Results
Data for the 17 patients is summarised in Tables 1,2: Demographic data and duration of clozapine therapy: Mean age was 43.7 years (range 29-60 years). Mean duration of clozapine treatment prior to referral was 8 years (range 2-15 years). Clozapine was stopped in two patients.

Immunoglobulin levels:
All 17 patients had panhypogammaglobulinaemia (all Immunoglobulin isotypes low or absent) at referral, or developed panhypogammaglobulinaemia while being followed up.
Mean immunoglobulin levels at referral were:

Susceptibility to infection, microbiology results and types of infections:
12 patients (70%) were prone to recurrent sinopulmonary infections, with one requiring multiple admissions to the intensive care unit (ICU).
Pathogens commonly isolated were haemophilus, moraxella and pseudomonas spp.

Lymphocytes subsets:
16 patients (94%) showed total lymphocyte counts within the normal reference range.
Lymphocyte subsets were variable: -All lymphocyte subsets were low in one patient with lymphoid hyperplasia.
-The CD8 count was low in 3 patients: o L6: treated for granulomatous lung disease, most likely to be granulomatous interstitial lung disease secondary to immunodefi ciency. -NK cells (CD16/56) were reduced in 7 patients. One was treated for refractory Hodgkin's lymphoma.

Other immunological investigations:
Mannose binding lectin (MBL) was found to be low in 3 of the 5 patients tested (60%).

Other clinical features and co-morbidities:
The following were each observed in 1 patient (6%): -granulomatous interstitial lung disease

Discussion
We describe 17 clozapine-treated patients referred with hypogammaglobulinaemia for which no other cause was evident.
In a study exploring the use of decreased total serum globulins as a surrogate marker for hypogammaglobulinaemia, 4 of 32 primary care patients found to be hypogammaglobulinaemic were being treated with clozapine [4]. A subsequent comparison between clozapine-treated and clozapine-naïve patients confi rmed an associated with hypogammaglobulinaemia, noting increased antibiotic usage and hospital admissions in the clozapine-treated group. The extent of the hypogammaglobulinaemia correlated with the duration of clozapine treatment [3]. The same group have reported the clinical and laboratory characteristics of clozapine-treated patients with schizophrenia referred to a national immunodefi ciency clinic revealling a B-cell signature resembling common variable immunodeficiency (CVID) [5].
Our report is the fi rst demonstration in England that clozapine-treated patients do present to specialist immunology There is evidence that the therapeutic effect of clozapine might depend on interaction with phosphatidylinositol-3kinase (PI3K) pathways [6][7][8]. Furthermore, PI3K signalling pathways are essential for the development and homeostasis of B cells [9,10]. Additionally, inherited defects of PI3K signalling result in immunodefi ciency [11]. Speculatively, therefore, altered function of PI3K pathways may be a mechanism for clozapine toxicity.

Suggestions & Conclusion
The need to monitor clozapine-treated patients for toxic effects on granulocytes is well-established. New evidence suggests that it might also be prudent to monitor immunoglobulin levels and maintain clinical vigilance for infection with polysaccharide-encapsulated organisms (which are of particular relevance to antibody defi ciency).
While there is tentative evidence that these changes may sometimes be reversible, the balance of risks may favour continuation of clozapine in patients who develop antibody deficiency. Ancillary treatments (e.g. antibiotics for acute infection, antibiotic prophylaxis, immunoglobulin replacement) may then become necessary.
Further research would be required to elucidate the mechanism of these effects.