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Letter to the Editor

Drs Lee and Remington Reply

Jimmy Lee, MBBS, MMED, and Gary Remington, MD, PhD

Published: April 27, 2016

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See letter by Lozano et al and article by Lee et al

Drs Lee and Remington Reply

To the Editor: Lozano et al1 raised 2 points related to our recent publication2 highlighting the association between clozapine and anemia. First, Lozano et al1 commented that the plasma clozapine levels in the group with anemia (771.7 ± 287.1 ng/mL) were above the therapeutic level and might lead to a toxic outcome and that perhaps smoking acted via cytochrome P450 1A2 (CYP1A2) to reduce plasma clozapine levels in the group without anemia. Our group did consider this possibility and had mentioned it in the discussion; however, the issue of an upper therapeutic limit for plasma clozapine levels remains open to debate.3 Regarding the relationship between plasma clozapine levels and side effects, there is circumstantial evidence for seizures, though this side effect appears more closely related to increases in the oral dosage.3 As highlighted by the authors,1 there is the recent evidence suggesting an association between plasma clozapine levels and metabolic side effects.4 There has been no consistent evidence linking plasma clozapine levels to agranulocytosis or neutropenia—commonly reported hematologic aberrations linked to clozapine.3

The relationship between smoking and plasma clozapine levels has been the subject of numerous reports.5 As expected, we did find differences in dose-adjusted plasma clozapine levels in our sample, with the group who smoked having significantly lower levels. Unfortunately, we did not have the required data to provide further insight into the relationship between plasma clozapine levels and incidence of anemia.

On the point of smoking as a protective factor for anemia, and as we have discussed, there is evidence to show that even in the non-mentally ill, smoking in itself leads to an up-regulation of hemoglobin.6 This is a physiological adaptation, and we have no reasons to speculate that the same will not occur in patients with serious mental illnesses. It is also possible that both mechanisms involving smoking acted synergistically, ie, the reduction of plasma clozapine levels, and hence reduced toxicity, and up-regulation of hemoglobin levels.

Second, we agree with Lozano and colleagues’ point on the possible link between high-sensitivity C-reactive protein (hs-CRP) and anemia.1 Anemia of inflammation, as stated in their letter, is sometimes known as anemia of chronic disease, which was discussed as a possibility in our discussion. The pathophysiology of anemia of chronic disease is complex and has been attributed to the direct effect of various cytokines on erythropoiesis.7 While elevated hs-CRP appears early in the course of clozapine treatment and is reportedly transient,8 the cases of anemia observed in our study were either recurrent or persistent. Again, since our study was naturalistic in nature and no inflammatory makers of acute phase proteins were measured, we are unable to conclude with certainty.

In summary, the available evidence we have was insufficient for us to attribute the observed anemia to clozapine alone, leaving us to discuss our findings broadly. Importantly, the studied population represents patients with treatment-resistant schizophrenia, and the findings might not be generalizable to all patients with schizophrenia. Nevertheless, we hope that findings from this study will raise awareness among clinicians and perhaps lead to further studies that might clarify the association between clozapine, smoking, and anemia.


1. Lozano R, Franco M, Marin R, et al. Anemia among schizophrenic patients: influence of clozapine and C-reactive protein. J Clin Psychiatry. 2016;77(0):000-000.

2. Lee J, Bies R, Bhaloo A, et al. Clozapine and anemia: a 2-year follow-up study. J Clin Psychiatry. 2015;76(12):1642-1647. PubMed doi:10.4088/JCP.14m09143

3. Remington G, Agid O, Foussias G, et al. Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold? Psychopharmacology (Berl). 2013;225(3):505-518. PubMed doi:10.1007/s00213-012-2922-7

4. Simon V, van Winkel R, De Hert M. Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? a literature review. J Clin Psychiatry. 2009;70(7):1041-1050. PubMed doi:10.4088/JCP.08r04392

5. Tsuda Y, Saruwatari J, Yasui-Furukori N. Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine. BMJ Open. 2014;4(3):e004216. PubMed doi:10.1136/bmjopen-2013-004216

6. Nordenberg D, Yip R, Binkin NJ. The effect of cigarette smoking on hemoglobin levels and anemia screening. JAMA. 1990;264(12):1556-1559. PubMed doi:10.1001/jama.1990.03450120068031

7. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011-1023. PubMed doi:10.1056/NEJMra041809

8. Löffler S, Löffler-Ensgraber M, Fehsel K, et al. Clozapine therapy raises serum concentrations of high sensitive C-reactive protein in schizophrenic patients. Int Clin Psychopharmacol. 2010;25(2):101-106. PubMed doi:10.1097/YIC.0b013e32833643fd

Jimmy Lee, MBBS, MMEDa,b,c

Gary Remington, MD, PhDc,d

aDepartment of General Psychiatry 1, Institute of Mental Health, Singapore

bOffice of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore

cSchizophrenia Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

dDepartment of Psychiatry, University of Toronto, Ontario, Canada

Potential conflicts of interest: Dr Lee is supported by the Singapore Ministry of Health’s National Medical Research Council under its Transition Award (Grant No.: NMRC/TA/002/2012). Dr Remington has received research support, consulting fees, or speaker’s fees from the Canadian Diabetes Association, the Canadian Institutes of Health Research, Hoffman-La Roche, Laboratorios Farmacéuticos Rovi, Medicure, Neurocrine Biosciences, Novartis Canada, Research Hospital Fund-Canada Foundation for Innovation, and the Schizophrenia Society of Ontario.

Funding/support: This work was supported in part through an Academic Health Science Center (Ontario, Canada) Alternate Funding Plan Innovation Fund Award (G.R.).

Role of the sponsor: The supporter was not involved in the design and conduct of the study; analysis and interpretation of the data; and preparation, review, or approval of the manuscript or this rejoinder letter to the editor.

J Clin Psychiatry 2016;77(4):e468

© Copyright 2016 Physicians Postgraduate Press, Inc.

Volume: 77

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