Dr Nielsen and Colleagues Reply

See letter by Woesner and Kanofsky and article by Nielsen et al

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Dr Nielsen and Colleagues Reply

To the Editor: We thank Drs Woesner and Kanofsky for commenting on our article, “Termination of Clozapine Treatment Due to Medical Reasons.”1 We fully acknowledge that nephritis/renal failure is a rare adverse effect of clozapine that warrants further attention. It seems that nephritis adds to a growing number of presumably dose-independent adverse drug reactions (ADRs) of clozapine with a possible immunologic origin, including, for example, colitis, pancreatitis, pericarditis, myocarditis, and polyserositis.2

These ADRs have in common an emergence within the first month of clozapine treatment and often with the presence of fever and flu-like symptoms. Some of these features overlap with or represent clozapine-induced fever, which is usually benign and transient, but which may also indicate marked immunologic activation.3

Several risk factors for these ADRs have been suggested. The presence of eosinophilia is considered an indication that these ADRs reflect an immunoglobulin E hypersensitivity reaction.4 However, eosinophilia can also occur as a benign and often transient phenomenon during clozapine treatment. For myocarditis, rapid initial titration rate of clozapine and cotreatment with sodium valproate have been suggested as relevant risk factors.5 Interestingly, 5 of 8 cases of clozapine-induced nephrititis/renal failure were cotreated with sodium valproate.6 Common for these possible risk factors is that they are based on low numbers of patients and have not been replicated.

We do not believe that the available data justify routine laboratory testing, such as troponins for myocarditis or serum creatinine for renal failure in the absence of suggestive clinical changes, as abnormal results will not confirm an etiologic relationship with the clozapine treatment. In addition, an even more complicated monitoring routine may prohibit some psychiatrists from prescribing clozapine. However, psychiatrists should pay extra attention in case of fever, flu-like symptoms, or eosinophilia during the first month of clozapine treatment and bear in mind that this phenomenon may affect any organs.

We agree that signs of these inflammatory adverse effects should lead to termination of clozapine. However, as clozapine is an effective antipsychotic drug, the highly clinically relevant question emerges: is clozapine rechallenge safe and meaningful?

Currently, the number of rechallenged patients is far too low to draw any firm conclusions. As Woesner and Kanofsky state, 2 of 2 rechallenged patients reexperienced clozapine-induced nephritis. However, a review by Manu et al7 found that clozapine rechallenge was successful in 3 of 4 cases of myocarditis. As these low numbers illustrate, it is highly important that any patient who experienced a serious/potentially life threatening ADR with clozapine who is later rechallenged is reflected in the literature, so that we can learn more about under which circumstances clozapine rechallenge is or is not safe.

Finally, we would like to emphasize that clozapine is highly underutilized and that further underutilization because of these very rare adverse effects should not occur.8 Clozapine is, under the right circumstances, a safe and frequently live-saving antipsychotic.9

References

1. Nielsen J, Correll CU, Manu P, et al. Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603-613. PubMed doi:10.4088/JCP.12r08064

2. R׸ge R, M׸ller BK, Andersen CR, et al. Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far? Schizophr Res. 2012;140(1-3):204-213. PubMed doi:10.1016/j.schres.2012.06.020

3. Kohen I, Afzal N, Hussain S, et al. Increases in C-reactive protein may predict recurrence of clozapine-induced fever. Ann Pharmacother. 2009;43(1):143-146. PubMed doi:10.1345/aph.1L467

4. Hatton JL, Bhat PK, Gandhi S. Clozapine-induced myocarditis: recognizing a potentially fatal adverse reaction. Texas Heart Institute journal/from the Texas Heart Institute of St Luke’s Episcopal Hospital. Tex Heart Inst J. 2015;42(2):155-157. doi:10.14503/thij-13-3633 PubMed

5. Ronaldson KJ, Fitzgerald PB, McNeil JJ. Clozapine-induced myocarditis, a widely overlooked adverse reaction [published online ahead of print April 11, 2015]. Acta Psychiatr Scand. PubMed doi:10.1111/acps.12416

6. Kanofsky JD, Woesner ME, Harris AZ, et al. A case of acute renal failure in a patient recently treated with clozapine and a review of previously reported cases. Prim Care Companion CNS Disord. 2011;13(3). PubMed doi:10.4088/pcc.10br01091

7. Manu P, Sarpal D, Muir O, et al. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? a systematic review of the published literature. Schizophr Res. 2012;134(2-3):180-186. PubMed doi:10.1016/j.schres.2011.10.014

8. Nielsen J, R׸ge R, Schjerning O, et al. Geographical and temporal variations in clozapine prescription for schizophrenia. Eur Neuropsychopharmacol. 2012;22(11):818-824. PubMed doi:10.1016/j.euroneuro.2012.03.003

9. Freudenreich O. Clozapine-induced myocarditis: prescribe safely but do prescribe [published online ahead of print April 11, 2015]. Acta Psychiatr Scand. PubMed doi:10.1111/acps.12425

Jimmi Nielsen, MDa,b

[email protected]

Peter Manu, MDc,d,e

John M. Kane, MDc,d,e

Christoph U. Correll, MDc,d,e

aDepartment of Psychiatry, Aalborg University Hospital, Aalborg, Denmark

bDepartment of Clinical Medicine, Aalborg University, Aalborg, Denmark

cThe Zucker Hillside Hospital, Psychiatry Research, North Shore-Long Island Jewish Health System, Glen Oaks, New York, New York

dAlbert Einstein College of Medicine, Bronx, New York

eHofstra North Shore-LIJ School of Medicine, Hempstead, New York

Potential conflicts of interest: Dr Nielsen has received speaker honoraria from HemoCue, Lundbeck, and BMS and research grants from H. Lundbeck and Pfizer. Dr Kane has been a consultant for Alkermes, Lilly, Forum, Forest, Genentech, Lundbeck, Intra-Cellular Therapies, Janssen, Johnson & Johnson, Otsuka, Reviva, Roche, and Sunovion; has received honoraria for lectures from Genentech, Janssen, Lundbeck, and Otsuka; and is a stock shareholder in MedAvante and Vanguard. Dr Correll has been a consultant for Abbvie, Actavis, Alkermes, BMS, Lilly, Genentech, Gerson Lehrman, Intra-Cellular Therapies, Janssen/Johnson & Johnson, Lundbeck, MedAvante, Medscape, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Supernus, and Takeda; has received grant/research support from American Academy of Child and Adolescent Psychiatry, BMS, Janssen/Johnson & Johnson, NIMH, Novo Nordisk, A/S Otsuka, Takeda, and the Thrasher Foundation; has received honoraria from Medscape; served on the advisory boards for Abbvie, Actavis, Alkermes, BMS, Lilly, Genentech, Gerson Lehrman, Intra-Cellular Therapies, Janssen/Johnson & Johnson, Lundbeck, MedAvante, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Supernus, and Takeda; and has provided expert testimony for Janssen. Dr Manu reported no potential conflicts relevant to the subject of this letter.

Funding/support: None reported.

J Clin Psychiatry 2015;76(12):1694-1695

dx.doi.org/10.4088/JCP.15lr10019a

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