Clozapine-induced neutropenia ❚ Case notes
Clozapine-induced neutropenia reversed by lithium
Devender Yadav MBBS, DPM, Simon Burton MBChB, FRANZCP, Chandan Sehgal MBBS, MRCPsych
Clozapine is effective in treating refractory cases of schizophrenia and schizoaffective disorder, however, it can induce the serious side-effect of neutropenia. There is an evolving evidence base in which lithium is used to increase the neutrophil and white cell count in patients who develop neutropenia from clozapine treatment, thus allowing clozapine treatment to continue. Dr Yadav et al. describe such a case.
n refractory Icases of schizo 10 affective disor /L 9 der, treatment 8 with clozapine has been found to be effica 6 cious and safe.1-3 However, clozap ine carries a risk of neutropenia 4 Green region and agranulocytosis. It is esti Amber region mated that around 2.7% of 2 Red region patients treated with clozapine develop neutropenia and around White blood cell count x10 0.8% of clozapine-treated patients 0 develop agranulocytosis.4 Mar Apr May Jun Jul Aug Sep Lithium increases the white cell 2015 2015 2015 2015 2015 2015 2015 count (WBC) and neutrophil Treatment dates on Clozaril count, both acutely5 and chroni cally.6 This tendency of lithium to Figure 1. White blood cell count during clozapine treatment increase the WBC (leucocytosis) is Presentation the inpatient unit and risk of self- harnessed in successfully treating Miss A, a 31-year-old caucasian neglect. She presented with irritabil neutropenia resulting from carba female first presented to psychiatric ity, delusions of erotomania, audi mazepine therapy and during can services at the age of 18 years with tory hallucinations (responding to cer chemotherapy.7 depression. Subsequently, from the unseen stimuli, hearing voices of The mechanism by which lith age of 18 years to 29 years, she had screaming babies), and delusions of ium increases the neutrophil multiple hospital admissions and persecution. She was on olanzapine count and total WBC is not com received various combinations of 15mg nocte and sodium valproate pletely understood and the effect psychotropic medications. She pre 500mg BD at the time of the admis is poorly quantified.7 However, sented with features of mania and sion and had been prescribed this various suggestions have been put psychosis and she was eventually combination of medications since forward: stimulation of GM-CSF diagnosed with schizoaffective psy December 2014. (granulocyte-macrophage colony chosis, which unfortunately was During her inpatient stay on the stimulating factor);8 demargina treatment resistant. unit a decision was made by the MDT tion;2 direct stem cell stimulation; She was admitted in March 2015 to increase the dose of olanzapine stimulation of cytokines, and to our low secure inpatient unit, fol and sodium valproate. However, this increased cortisol production have lowing a relapse and also because of was not effective and a decision was been suggested. the risks she posed to others. Her made to start her on clozapine. Olan A case report is now described risks were predominantly threats of zapine 20mg was gradually tapered in which lithium was used to reverse violence towards her ex-partner, and stopped; sodium valproate was clozapine-induced neutropenia. impulsivity, risks of absconding from continued at 1g BD. www.progressnp.com Progress in Neurology and Psychiatry May/June 2016 13 Case notes ❚ Clozapine-induced neutropenia
In order to initiate clozapine, patients must have a baseline WBC 6 count of 4.0×109/L and a neutro phil count of 2.5×109/L. If the
patient has a ‘red’ result, ie leucope /L 9 nia (WBC <3×109/L) or neutrope 4 nia (neutrophils <1.5×109/L), clozapine should not be given. Total WBC on the 17.03.15 was Green region 2 6.6×109/L, the neutrophil count Amber region 9 Neutrophil x10 was 3.3×10 /L – both within nor Red region mal limits. The dose of clozapine was grad ually increased to 50mg a week later, 0 Mar Apr May Jun Jul Aug Sep and later to 75mg on 02.04.15 and 2015 2015 2015 2015 2015 2015 2015 gradually built up to 275mg. Total Treatment dates on Clozaril WBC in March and April ranged 9 9 from 4.8×10 /L to 6.4×10 /L (see Figure 2. Neutrophil count during clozapine treatment Figure 1) and the neutrophil count ranged from 2.2×109/L to also increase the WBC levels. This 0.27mg/L and 0.19mg/L respec 3.5×109/L (see Figure 2). Serum plan was discussed with the patient tively on the 18.08.15. clozapine and norclozapine levels at and a written consent was obtained. The patient did respond favour 275mg on 27.04.15 were 0.33mg/L Prior to starting lithium, the ably to the combination of lithium and 0.20mg/L, respectively. MDT suggested decreasing the dose and clozapine. Her delusions of of clozapine to see if this increased erotomania had decreased consid Diagnosis and treatment the neutrophil levels: clozapine was erably and also her delusions of The neutrophil count unfortunately gradually reduced to 225mg on paranoia and persecution had also started to decrease from the 30.05.15. The neutrophil count was decreased in intensity. She was less 06.05.15. The neutrophil count on 1.8×109/L on 30.05.15. However, irritable. The improvement in her 06.05.15 and 26.05.15 was 1.9×109/L this was not effective and lithium clinical response and a decrease in and the clozapine and norclozapine was thus started on 02.06.15 by cross her level of risks led to her moving levels at 275mg on the 27.05.15 were tapering with the sodium valproate, on in her care pathway. She was 0.25mg/L and 0.14mg/L respectively. which was eventually stopped. transferred from our low secure Twice weekly WBC was being The neutrophil count decreased hospital to a locked rehabilitation done to safeguard the patient, and to 1.5×109/L on 05.06.15. The dose unit in October 2015. other potential causes of decreased of clozapine was further reduced to neutrophils were ruled out by the 150mg on 06.06.15 and the daily Discussion medical team. She had no signs of dosage of lithium carbonate was Olanzapine, and rarely sodium val infection or inflammation. Neu gradually built up to 750mg in proate, can potentially cause a low tropenia can arise because of fac divided doses (250mg mane and neutrophil count. However, the tors unrelated or indirectly related 500mg nocte). Gradually the neutro patient was on olanzapine and to clozapine treatment. These phil crept up to 2.1×109/L on the sodium valproate combination include benign ethnic neutrope 08.06.15 and reached 2.6×109/L on since December 2014, so it looks nia, concomitant drug therapy, the 26.06.15. unlikely that these medications co-existing medical conditions and The WBC ranged from 5.8×109/L caused neutropenia. drug interactions. to 7.22×109/L and the neutrophil It is well documented that clo The neutrophil count was count ranged from 2.45×109/L to zapine can potentially cause blood 1.8×109/L on 30.05.15 and 02.06.15. 5.69×109/L from June to September dyscrasias. There are reports that A decision was made by the multidis 2015 and were within normal limits. clozapine can potentially cause an ciplinary team (MDT) to start the The serum lithium level was increase in WBC (leucocytosis).9,10 patient on lithium instead of sodium 0.5mmol/L on the 13.08.15 on 750mg However, this does not apply in the valproate. Lithium would not only of lithium carbonate in divided above case. help with the affective component doses. The serum clozapine and nor In the above case, only when clo of the disorder, but would hopefully clozapine on 150mg of clozapine was zapine was introduced, a decrease
14 Progress in Neurology and Psychiatry May/June 2016 www.progressnp.com Clozapine-induced neutropenia ❚ Case notes
in neutrophil count (neutropenia) Also, because lithium is not naturalistic 48-month follow-up study. J Clin was noted on full blood count licensed for use to increase the Psychiatry 2003;64(4);451–8. 2. Small JK, Klapper MH, Malloy FW, et al. Tol (FBC). A reduction in the clozap white cell count, psychiatrists and erability and efficacy of clozapine combined ine dose was not effective in increas prescribers should be aware of the with lithium in schizophrenia and schizoaf ing the neutrophil count. In medico-legal implications of pre fective disorder. J Clin Psychopharmacol 2003; 7 23:223–8. hindsight, it was felt that the clini scribing lithium off-label. 3. Bender S, Linka T, Wolstein J, et al. Safety cal decision to decrease the dose of The above case report adds to and efficacy of combined clozapine-lithium clozapine was not evidence based. a growing body of evidence pharmacotherapy. Int J Neuropsychopharma- col 2004;7:59–63. The risk of clozapine-induced neu (mostly case reports and case 4. Munro J, O’Sullivan D, Andrews C, et al. tropenia is not dose related and it series), in which lithium is used to Active monitoring of 12,760 clozapine recip may differ between individuals and increase neutrophil and white cell ients in the UK and Ireland. Beyond pharma covigilance. Br J Psychiatry 1999;175:576–80. also between milder and severe count in patients who developed 5. Lapierre G, Stewart RB. Lithium carbonate forms of marrow suppression. The neutropenia from clozapine treat and leukocytosis. Am J Hosp Pharm 1980; mechanism of clozapine-induced ment, thus allowing clozapine 37(11):1525–8. 13-16 6. Carmen J, Okafor K, Ike E. The effects of neutropenia is unclear and it is pos treatment to continue. lithium therapy on leukocytes: a 1-year follow sible that a direct cytotoxic effect up study. J Natl Med Assoc 1993;85(4):301–3. and immune-mediated mechanism Conclusion 7. Paton C, Esop R. Managing clozapine- 11,12 induced neutropenia with lithium. BJ Psych may play a role. The clozapine- Lithium can be used successfully to Bulletin 2005;29:186–8. DOI:10.1192/pb. induced neutropenia only imp treat clozapine-induced neutrope 29.5.186. roved when lithium was added. nia. This requires close clinical 8. Ozdemir MA, Sofuoglu S, Tanrikulu G, et al. Lithium-induced hematological changes in The combination of clozapine monitoring of patients. Also dis patients with bipolar affective disorder. Biol and lithium is beneficial in some cussing with the patient and their Psychiatry 1994;35:210–3. cases. However, the combination close relatives and obtaining their 9. Lambertenghi Deliliers G. Blood dyscrasias in clozapine-treated patients in Italy. Haema- warrants close haematological, bio informed written consent before tologica 2008;85:233–7. chemistry, serological and clinical initiating an off-label prescription 10. Madhusoodanan S, Cuni L, Brenner R, et monitoring, as lithium does not of lithium is paramount in order to al. Chronic leucocytosis associated with clo zapine: a case series. J Clin Psychiatry 2007; protect against agranulocytosis and safeguard the prescriber and pre 68:484–8. can lead to an increased side- effect vent any medico-legal issues. 11. Whiskey E, Taylor D. Restarting clozapine burden. Clinicians need to be after neutropenia: evaluating the possibili ties and practicalities. CNS Drugs 2007;21(1): mindful of lithium toxicity and also Dr Yadav is an Associate Specialist in 25–35. neurological side-effects. Psychiatry; Dr Burton is a Consultant 12. Gerson SL. Clozapine – deciphering the There is an evolving evidence Psychiatrist and Dr Sehgal is a Consult- risks. N Eng J Med 1993;329:204–5. 13. Suraweera C, Hanwella R, De Silva V. Use base in which lithium is used to ant Forensic Psychiatrist, all at Ludlow of lithium in clozapine-induced neutropenia: increase neutrophil and white cell Street Healthcare Group, Heatherwood a case report. BMC Res Notes 2014;7:635. count. The mechanism by which Court Hospital, Pontypridd, Wales. 14. Blier P, Slater S, Measham T, et al. Lithi um and clozapine-induced neutropenia/ lithium increases the neutrophil agranulocytosis. Int Clin Psychopharmacol count and total WBC is not com Declaration of interests 1998;13(3):137–40. pletely understood and the effect is No conflicts of interest were declared. 15. Rosli ANM, Subbiah R, Maniam T. Clozap 7 ine re-challenge with lithium supplementa poorly quantified. tion following clozapine-induced neutrope Neutrophilia does not seem to References nia. ASEAN J Psychiatry 2014;15(1):90–2. be dose related although a mini 1. Ciapparelli C, Dell’Osso L, Bandettini de Pog 16. Palominao A, Kukoyi O, Xiong GL. gio A, et al. Clozapine in treatment-resistant Leukocytosis after lithium and clozapine mum serum level of 0.4mmol/L patients with schizophrenia, schizoaffective combination therapy. Ann Clin Psychiatry may be required.14 disorder, or psychotic bipolar disorder: a 2010;22(3):205–6.
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