Discussion
The current study represents, to the best of our knowledge, the first systematic study of myocardial function in asymptomatic patients on long-term clozapine treatment for schizophrenia. We have identified mildly impaired cardiac function in patients with schizophrenia, which was more severe in patients taking clozapine, whether measured by conventional parameters of LVEF or by assessment of myocardial function by GLS. We also report for the first time that, in patients taking clozapine, the subclinical impairment of LV function is independently associated with systemic inflammation characterised by neutrophilia and with low HDL-C.
Depending on the definition used to define subclinical cardiomyopathy, between 9% (LVEF<50%) and 49% (GLS>−16.6%, ie, below 2 SDs or the 95% CI of the normal controls) of patients on long-term clozapine treatment had at least some degree of LV systolic impairment. This may be a conservative estimate given that published normal values for LV GLS are reported to be −18.6±0.1%.18 Among non-clozapine-treated patients with schizophrenia, 14% had impaired GLS based on the above definition. This subclinical LV dysfunction was global (no patients had evidence of segmental dysfunction as is seen after myocardial infarction), was asymptomatic and was not associated with an elevation of HsTropT or with ECG abnormality. There was no evidence of greater dysfunction in those patients having received clozapine for longer duration, suggesting this is not necessarily progressive over time.
The precise mechanism of clozapine-induced muscle injury is not known; however, it is most likely that that the changes are due to direct toxicity of clozapine on the myocardium and not myocarditis as these patients were apparently well and no patient had clinical, ECG or biochemical history to suggest myocarditis. Clozapine is an antagonist of calmodulin, which regulates the contractile response of striated muscles via its effects on calcium uptake, DNA synthesis, neuromuscular transmission and various kinases. Myotoxicity and neurotoxicity have been reported in patients on long-term clozapine treatment based on electromyography, nerve conduction and muscle biopsy studies.22 ,23 Raised serum CK levels, a marker of muscle damage, have been reported in 14–78% of patients on clozapine treatment, independent of dose.22 ,23 In our study, 14 of the 100 patients in the clozapine group had raised CK, compared with 2 of 20 controls (p=ns). Similar mechanistic pathways may contribute to clozapine-induced cardiomyopathy. The lack of significant association of NT-proBNP with GLS in multivariate analysis (p=0.08) may be due to sample size. However, as our echo data found that impairment in LV contractility was a more striking abnormality than chamber dilation with subsequent NT-proBNP release,24 the lack of dilation and myocardial stretch explain the relatively modest NT-proBNP release in our cohort.
Our results suggest that the subclinical cardiac dysfunction we have observed with clozapine in this study is not rare and idiosyncratic, as is the incidence of acute myocarditis. Rather, this appears to be a common occurrence affecting a high proportion of patients receiving clozapine, and unlike myocarditis, is unrelated to levels of HsTropT. As some degree of subclinical cardiac impairment may be common in patients receiving clozapine, its detection may not necessarily warrant clozapine cessation. Indeed, premature clozapine cessation can have devastating consequences for effectively treated patients with schizophrenia. Instead, prevention of additional cardiac injury related to recreational drugs such as alcohol and amphetamines, the primary prevention of ischaemic events, and in some circumstances the start of drugs proven useful in the treatment of cardiac dysfunction in other settings (such as ACE inhibitors and β blockers) are likely to be important treatment goals in these patients.
The mechanism of clozapine-induced leucocytosis and neutrophilia is not clear, but increases in granulocyte colony-stimulating factor, tissue necrosis factor-α and interleukin-6 (IL-6) have been proposed.25 In patients with schizophrenia, a significant positive correlation had been reported between plasma IL-6 levels and illness duration.26 IL-6 is a potent promoter of neutrophil release from non-circulating marginal pool into the circulation, resulting in neutrophilia.27 Wasti et al28 observed marked leucocytosis and neutrophilia among rats treated with clozapine over a 3-week period. Cytotoxic reactive metabolites of clozapine may play an important role in the pathogenesis of clozapine-induced neutrophilia. Given the correlation we observed between neutrophilia and cardiac dysfunction, it is possible that the same metabolites promote myocardial dysfunction and neutrophilia. There were active smokers among the patients receiving clozapine, and smoking has been shown to be associated with increases in total and differential leucocyte counts.29 However, smoking was not an independent predictor of impaired LV GLS on multivariate analysis in the current study and there was no interaction between smoking and neutrophilia in our modelling.
Studies in patients with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis have shown an inverse correlation between HDL-C levels and levels of several proinflammatory markers, with HDL-C having anti-inflammatory properties.30 We found that patients on clozapine treatment had reduced HDL-C compared with patients in the non-clozapine group and healthy controls, and reduced HDL-C was an independent predictor of impaired LV contractility. This supports the possibility that a heightened inflammatory state explains the reduced HDL-C levels, and that the subclinical cardiomyopathy of patients with schizophrenia receiving clozapine may be inflammatory in origin. Whether low HDL-C provides unique prognostic or mechanistic information regarding clozapine-related myocardial dysfunction requires further study.
Clozapine-related tachycardia occurs in approximately 25% of patients, with average heart rate increases 10–15 bpm reported.31 The mechanism of tachycardia appears to be due to the anticholinergic effects of clozapine, resulting in vagal inhibition.32 Persistent tachycardia can result in tachycardia-induced cardiomyopathy.33 In our study, although the mean resting heart rate was raised in patients receiving clozapine, it was nonetheless less than 100 bpm. In addition, the resting heart rate did not correlate with inflammatory markers such as neutrophil count or hsCRP. Further studies are required to determine the effects of heart rate reduction with pharmacological agents on changes in LV contractility among patients receiving clozapine treatment.
In our study, although patients with schizophrenia receiving non-clozapine antipsychotic medications had less severe impairment in LV systolic function than did patients receiving clozapine, the degree of impairment remained significant when compared with healthy controls in terms of Simpson's EF (p=0.03) and GLS (p=0.009). Similar to clozapine, non-clozapine antipsychotic medications have been shown to result in significant weight gain. The development of metabolic syndrome, obesity and diabetes have all been shown to be associated with clinical and subclinical cardiomyopathy.34 ,35 However, in a recent study of 2D strain in patients with diabetes and metabolic syndrome, under resting conditions, LV strain and LVEF were identical in patients with and without metabolic syndrome.36 This suggests that the degree of impairment we have observed in the present study is unlikely to be adequately explained by associated metabolic changes alone and may have contributions from the direct effects of antipsychotic medications (clozapine and non-clozapine).
The two main goals of cardiac monitoring are to exclude clozapine-induced acute myocarditis and to monitor for long-term cardiomyopathy. The presence of abnormal clinical, echocardiographic or biochemical findings consistent with myocarditis (new onset tachycardia with HR>120 bpm, raised hsCRP, HsTropT, acute deterioration in LVEF and/or systemic symptoms suggestive of myocarditis or cardiac failure) necessitates immediate cardiology review specifically to consider the cessation of clozapine and start of cardioprotective drugs such as β blockers and ACE inhibitors. In the absence of myocarditis, the protocol published by Ronaldson et al37 appears appropriate. Clinical evaluation, ECG and echocardiography are routinely performed prior to treatment and repeated at 3 months, 12 months, 2 years, 5 years and 10 years following the start of clozapine to assess for impaired and/or deteriorating cardiac function. If impaired LV function is identified, an individualised approach is required for each patient in consultation with treating psychiatrists. Treatment options under these circumstances include cardioprotective medications such as ACE inhibitors and β blockers, mild gradual reduction of clozapine dose and more frequent review to assess cardiac response to treatment.