Why is clozapine unique?

The questions as to why clozapine is unique has invited significant interest in psychiatry circles, and clinicians and researchers ponder about clozapine’s intriguing portfolio as an antipsychotic agent. On the positive side, it is the gold standard medication for treatment-resistant schizophrenia, but its use is limited due to the risk of serious side-effects like agranulocytosis. While divergence in receptor selectivity and binding compared to other antipsychotics is proposed as the mechanism for efficacy (Kapur and Remington, 2001), this does not fully explain how such interactions translate into clinical consequences – be it therapeutic response or side-effects. Delving into other hypotheses to explain clozapine’s uniqueness, we were intrigued by recent reviews (Drzyzga et al., 2006; Roge et al., 2012) discussing clozapine’s immunomodulating role which could explain both its efficacy and unusual adverse effect profile.

In this journal, there have been recent reports of unique clozapine-related side-effects (Mohan et al., 2013). The question is whether there is a unifying explanatory model linking the various rare clozapine-related adverse effects. Roge et al. (2012) propose that some of the unique side-effects of clozapine like agranulocytosis, myocarditis, pancreatitis, benign fever, and serositis are immune mediated. Of note, many of the above clinical syndromes are noted within the first few weeks of commencing clozapine treatment but tend to dissipate over time.

Clozapine has been shown to modulate immune messengers (cytokines) differently when compared to typical agents like chlorpromazine or other atypical medications like olanzapine. There are consistent reports of clozapine increasing the expression of pro-inflammatory cytokines like tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6). Clozapine also increases sIL-2R which binds and inactivates interleukin 2 (IL-2) thereby exerting an immunosuppressant effect (Drzyzga et al., 2006). Chlorpromazine tends to reduce TNFα levels (Pollmächer et al., 2000) and olanzapine has no effects on IL-6, sIL-2R, or TNFα (Drzyzga et al., 2006).

One could speculate that early in the course of treatment clozapine is pro-inflammatory and this contributes to both positive and negative consequences. Pollmächer et al. (2000) suggest that slight increases in TNFα could be therapeutically desired compared to the opposite effect observed with chlorpromazine. Increases in IL-6 levels are positively correlated with fever, but protracted treatment for 4 weeks dropped IL-6 to near normal levels (Drzyzga et al., 2006). Maes et al. (1997) suggest that clozapine has complex in-vivo immunomodulatory effects, with pro- inflammatory effects (e.g. increased IL-6) and immunosuppressive activities (e.g. increased IL-1RA and Clara cell protein 16). It is possible that an initial pro-inflammatory action explains the early side-effects (agranulocytosis, myocarditis, fever, etc.) but clozapine’s overall immunosuppressive effect contributes to its superior clinical effect compared to other antipsychotic medications.

Recently, there has been a renewed interest in the role of inflammation in the pathogenesis of schizophrenia. Enhanced pro-inflammatory activity may be particularly prominent in the early phase of schizophrenia (Meyer et al., 2011). An imbalance between the blunted cell-mediated (type 1) and activated humoral (type 2) immune responses has been proposed as an immunological mechanism underlying the disorder. Antipsychotic medications have a “balancing” effect on the type 1 and 2 responses although further research is warranted (Müller et al., 2013). In the context of this immune hypothesis, studies have now begun to investigate the potential role of non-steroidal anti-inflammatory drugs (NSAIDs) in reducing schizophrenia symptom severity (Sommer et al., 2012).

Altered immunological parameters in schizophrenia and clozapine’s unique immunomodulatory effects might shed light on how clozapine may exert its unique effects particularly in later stages of the disease when the disease process itself may have altered the immunological milieu. Further studies comparing longitudinal changes in inflammatory markers with clozapine and other antipsychotics need to be conducted to scrutinize the factors that set apart clozapine’s immunomodulatory role. This may lead to specific cytokine modulating drugs that can deliver the positives of clozapine without the attendant risks of immune mediated effects like agranulocytosis. Treatment resistance may be an immune mediated subset and characterizing the cytokine map of this population may enable early intervention before a chronic inflammatory state emerges. The above discussion also raises interesting questions as to whether NSAIDs should be considered as a prophylactic measure (for the first few weeks) following initial commencement of clozapine to prevent the side-effects such as agranulocytosis, myocarditis, and fever which may be related to a pro-inflammatory cascade triggered by clozapine.

We recognize that the interaction between the immune system, medications, pathophysiology, course of illness, triggering factors (e.g. infections), and associated factors (e.g. smoking) is a complex one. As such, any proposed causal hypotheses should be interpreted with caution. However, science progresses with a curious examination of associations, and clozapine’s interplay with the immune system is worth exploring.

See Letter by Mohan et al., 2013, 47(6): 586–587.