Bipolar Disorder: Open Access
Open Access

Case Report: Sodium Valproate-Induced Neutropenia in a Patient with Bipolar Disorder

Rajagopalan Arvind^*, Lim Shuli, Chan Christopher Yi Wen, Mok Yee Ming and Chandwani Nisha ^*Correspondence: Rajagopalan Arvind, Institute of Mental Health, Buangkok Green Medical Park, 10 Buangkok View, 539747-Singapore, Singapore, Tel: 63892000, Fax: 63851054, Email:

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Background

Sodium valproate is a commonly used medication for both seizure-control in patients with epilepsy as well as mood stabilization in patients suffering from bipolar disorder. It can cause various hematological dyscrasias, the most common of which is thrombocytopenia [1].

From our literature review, we found several case-reports of sodium valproate-related neutropenia (a reduction in absolute neutrophil count to under 1,500/μL) [2-7]. Most of these case reports were in pediatrics and epilepsy. Few reported on sodium valproate-related neutropenia in bipolar disorder [8,9]. We present the case of a middle-aged gentleman, previously stable for many years on sodium valproate, who developed neutropenia after being restarted on it following a period of non-compliance to treatment. We also discuss the possible mechanisms and management of sodium valproate-induced neutropenia.

Case Report

We present the case of a 52-year-old Chinese man with a known history of bipolar disorder, who was maintained on sodium valproate 1500 mg and risperidone 1 mg nightly for several years without requiring admissions. He was brought into the emergency department for a manic relapse, following a period of non-compliance. Sodium valproate was restarted at 500 mg nightly and he was admitted for further treatment. Subsequently, it was increased to 1000 mg nightly and risperidone 0.5 mg nightly was added. Routine blood tests were done the next morning, including fasting glucose and lipids, liver panel, renal panel, thyroid function tests and full blood count (FBC), which showed neutropenia (White cell count (WCC) 2,900/μL, Neutrophils 1,020/μL). Other cell lines were unaffected (Hemoglobin 13.5 g/dL, Platelets 247/μL), and the other blood tests were unremarkable. The patient did not exhibit any signs of ongoing infection (such as dental caries), hematological malignancies (such as hepatosplenomegaly) or nutritional deficiencies (such as peripheral neuropathy) upon physical examination. He had no significant past medical or family history. As the neutropenia was not severe (<1,000/μL) the decision was made to reduce the sodium valproate dose back to 500 mg nightly. FBC and serum valproate levels were taken two days later. The valproate level was 56 mg/L and the neutropenia resolved (WCC 4,800/μL, Neutrophils 2,450/μL). Further history revealed that he had been taking clarithromycin for an upper respiratory tract infection prior to admission. Considering that clarithromycin has also been linked to neutropenia [10], and that he was relatively well on sodium valproate before, the decision was made to increase the dose back to 1000 mg nightly with frequent FBC monitoring, as he remained symptomatic for mania. However, a subsequent FBC showed neutropenia again (WCC 3,200/μL, Neutrophils 1,210/ μL), and the dose was reduced back to 500 mg. The neutropenia was sustained, despite the reduction in dose, two days later (WCC 3,200/μL, Neutrophils 1,070/μL), and sodium valproate was discontinued. Other investigations for neutropenia, including B12 and Folate levels and a peripheral blood film, were unremarkable. Repeat liver and renal function tests were also unremarkable. Repeat FBCs on days 17 (WCC 3,800/μL, Neutrophils 1,500/μL), 19 (WCC 4,100/μL, Neutrophils 1,600/μL) and 27 (WCC 4,100/μL, Neutrophils 1,800/μL) postadmission showed recovery of WCC and neutrophil counts. Table 1 and Figure 1 below illustrate the relationship between the patient’s daily sodium valproate doses and his measured neutrophil counts.

Table 1: Neutrophil counts and daily Sodium Valproate doses during the course of admission.

Figure 1. Neutrophil counts vs daily sodium valproate doses.

Although there are case reports suggesting risperidone as a potential cause of neutropenia [11,12], this seems less likely as the neutropenia resolved despite the progressive increase in risperidone dose, similar to a previously reported case [9]. Sodium valproate seems to be the most likely cause of the patient’s neutropenia due to the temporal relationship between its administration and the neutropenia, as illustrated in Figure 1. It was decided not to restart sodium valproate. An adverse drug event report was filed in the local Critical Medical Information System to alert the Health Sciences Authority and other healthcare providers of this potential adverse reaction. The patient was eventually stabilized on a combination of 6 mg of risperidone and 5 mg of aripiprazole. As he remained afebrile, non-toxic and maintained neutrophil counts above 1000/μL, Granulocyte Colony Stimulating Factor (G-CSF) and broad-spectrum antibiotics were not indicated.

Discussion

In our literature review, we did not find any guidelines specific to the management of sodium valproate-related neutropenia in bipolar disorder. The mechanism behind sodium valproateinduced neutropenia is poorly understood. The first study to report this phenomenon was unable to detect antibodies against neutrophils in the patient ’ s serum [3]. Direct bone-marrow suppression has been proposed as a mechanism, with one casereport finding a dose-dependent relationship between sodium valproate dosage and bone-marrow suppression [13,14]. However, findings from bone-marrow biopsies in subsequent case reports are contrasting, with one report finding arrest of the myeloid maturation process in a 75-year-old patient ’ s bone marrow [7], and another finding no abnormalities in a 2-yearold’s bone-marrow [6]. In our case, we were not able to ascertain a relationship between serum valproate levels and neutropenia, as only a single valproate level was checked on day 5 postadmission. The relationship between the two is unclear, and studies have found that neutropenia may occur even with subtherapeutic serum valproate levels [15].

The main complication of neutropenia is secondary infection. Though patients can be asymptomatic and afebrile, it is important to monitor for signs of infection such as dental caries or abscesses, as this can be a marker of poor bone-marrow reserve and increases the risk of life-threatening sepsis. A fever should always be considered a sign of infection, as these patients may lack localizing symptoms [16]. In at least two of these cases, patients developed serious complications and co-morbidities that required intensive treatment and administration of G-CSF for recovery of neutrophil levels [5,7]. G-CSF is generally used prophylactically for the reduction in risk of infection in patients with lympho/myeloproliferative disorders, receiving hematopoietic stem-cell/bone-marrow transplantation or undergoing chemotherapy, with a greater than 20% risk of febrile neutropenia [17,18]. It is United States Food and Drug Administration (FDA) approved for the above indications and severe chronic neutropenia [18,19]. There are currently no guidelines for the use of G-CSF in drug-induced neutropenia, though it is suggested that it be avoided except in cases of recurrent infections, regardless of the severity of the neutropenia [16]. Some studies have suggested a neutrophil count of less than 100/μL as an indication for G-CSF in drug-induced neutropenia [20,21].

The safest approach to managing any severe drug-induced neutropenia would be to discontinue the most probable culprit drug [22]; the neutropenia is expected to resolve within one to four weeks after [5-7]. There are currently no guidelines to address whether the suspected drug should be withheld permanently or subsequently re-challenged. A recent systemic review suggested that for cases with mild neutropenia, continuation of the implicated drug could be considered, with strict monitoring. The author also suggests for temporary cessation of the drug and reinstatement once neutrophil count normalises for cases with moderate neutropenia, and that alternative agents should be used for severe cases [22]. Local guidelines also recommend annual checks of FBCs for stable patients on sodium valproate [23,24].

Conclusions

In conclusion, we found a significant lack of literature on sodium valproate-induced neutropenia. There are patients with bipolar disorder who may greatly benefit from the long-term use of sodium valproate, and it is one of the first line medications for the acute and maintenance treatment of bipolar disorder. This is hence an area that requires significant attention, given the potential severity of neutropenia and the relatively high frequency of sodium valproate prescription for bipolar disorder, and will require research utilizing large national registries and databases.

Declarations

Consent for publication

The subject of this case-report has consented to the publication of this report.

Availability of data and material

All data generated or analysed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Arvind Rajagopalan conceived the original idea for the manuscript. Arvind Rajagopalan, Shuli Lim, Christopher Yi Wen Chan, Yee Ming Mok and Nisha Chandwani contributed to the writing and proofreading of the final manuscript. The final manuscript was discussed and approved by all authors.

References

1. Conley EL, Coley KC, Pollock BG, DaPos SV, Maxwell R, Branch RA. Prevalence and risk of thrombocytopenia with valproic acid: experience at a psychiatric teaching hospital. Pharmacotherapy. 2001;21(11):1325-1330.
2. https://www.uptodate.com/contents/drug-induced-neutropenia-and-agranulocytosis
3. Jaeken J, Van Goethem C, Casaer P, Devlieger H, Eggermont E, Pilet M. Neutropenia during sodium sodium valproate treatment. Arch Dis Child. 1979;54(12):986.
4. Symon DN, Russell, G. Sodium sodium valproate and neutropenia. Arch Dis Child. 1983;58(3):235.
5. Vesta KS, Medina PJ. Valproic acid–induced neutropenia. Ann Pharmacother. 2003;37(6):819-821.
6. Kohli U, Gulati, S. Sodium valproate induced isolated neutropenia. Indian J Pediatr. 2006;73(9):844-844.
7. Hsu HC, Tseng HK, Wang SC, Wang YY. Valproic acid-induced agranulocytosis. Int J Gerontol. 2009;3(2):137-139.
8. Chakraborty S, Chakraborty J, Mandal S, Ghosal MK. A rare occurrence of isolated neutropenia with valproic acid: a case report. J Indian Med Assoc. 2011;109(5):345-346.
9. Hung WC, Hsieh MH. Neutropenia associated with the comedication of quetiapine and valproate in 2 elderly patients. J Clin Psychopharmacol. 2012;32(3):416-417.
10. Jacobs P, Conforti A, Wood L, Kiuru A, Jones GO, Woolf D. Immune agranulocytosis and clarithromycin. Hematology. 2004;9(4):291-296.
11. Manfredi G, Solfanelli A, Dimitri G, Cuomo I, Sani G, Kotzalidis GD, et al. Risperidone-induced leukopenia: a case report and brief review of literature. Gen Hosp Psychiatry. 2013;35(1):102e3-6.
12. Kailasam VK, Chima V, Nnamdi U, Sharma K, Shah K. Risperidone-induced reversible neutropenia. Neuropsychiatr Dis Treat. 2017;13:1975-1977.
13. Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol. 2000;22(1):62-65.
14. Watts RG, Emanuel PD, Zuckerman KS, Howard TH. Valproic acid-induced cytopenias: evidence for a dose-related suppression of hematopoiesis. J Pediatr. 1990;117(3):495-499.
15. Storch DD. Severe leukopenia with sodium valproate. J Am Acad Child Adolesc Psychiatry. 2000;39(10):1208-1209.
16. https://www.uptodate.com/contents/management-of-the-adult-with-non-chemotherapy-induced-neutropenia
17. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015;33(28):3199-3212.
18. http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf
19. Mhaskar R, Clark OAC, Lyman G, Botrel TEA, Paladini LM, Djulbegovic B. Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database Syst Rev. 2014;(10).
20. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med. 2007;146(9):657-665.
21. Andrès E, Maloisel F, Kurtz JE, Kaltenbach G, Alt M, Weber JC, et al. Modern management of non-chemotherapy drug-induced agranulocytosis: a monocentric cohort study of 90 cases and review of the literature. Eur J Intern Med. 2002;13(5):324-328.
22. Andrès E, Lorenzo Villalba N, Zulfiqar AA, Serraj K, Mourot-Cottet R, Gottenberg JE. State of art of idiosyncratic drug-induced neutropenia or agranulocytosis, with a focus on biotherapies. J Clin Med. 2019;8(9):1351.
23. https://www.moh.gov.sg/docs/librariesprovider4/guidelines/mohcpg_bipolar-disorder_booklet.pdf
24. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, et al. Canadian network for mood and anxiety treatments (CANMAT) and international society for bipolar disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2): 97-170.

References

1. Conley EL, Coley KC, Pollock BG, DaPos SV, Maxwell R, Branch RA. Prevalence and risk of thrombocytopenia with valproic acid: experience at a psychiatric teaching hospital. Pharmacotherapy. 2001;21(11):1325-1330.
2. https://www.uptodate.com/contents/drug-induced-neutropenia-and-agranulocytosis
3. Jaeken J, Van Goethem C, Casaer P, Devlieger H, Eggermont E, Pilet M. Neutropenia during sodium sodium valproate treatment. Arch Dis Child. 1979;54(12):986.
4. Symon DN, Russell, G. Sodium sodium valproate and neutropenia. Arch Dis Child. 1983;58(3):235.
5. Vesta KS, Medina PJ. Valproic acid–induced neutropenia. Ann Pharmacother. 2003;37(6):819-821.
6. Kohli U, Gulati, S. Sodium valproate induced isolated neutropenia. Indian J Pediatr. 2006;73(9):844-844.
7. Hsu HC, Tseng HK, Wang SC, Wang YY. Valproic acid-induced agranulocytosis. Int J Gerontol. 2009;3(2):137-139.
8. Chakraborty S, Chakraborty J, Mandal S, Ghosal MK. A rare occurrence of isolated neutropenia with valproic acid: a case report. J Indian Med Assoc. 2011;109(5):345-346.
9. Hung WC, Hsieh MH. Neutropenia associated with the comedication of quetiapine and valproate in 2 elderly patients. J Clin Psychopharmacol. 2012;32(3):416-417.
10. Jacobs P, Conforti A, Wood L, Kiuru A, Jones GO, Woolf D. Immune agranulocytosis and clarithromycin. Hematology. 2004;9(4):291-296.
11. Manfredi G, Solfanelli A, Dimitri G, Cuomo I, Sani G, Kotzalidis GD, et al. Risperidone-induced leukopenia: a case report and brief review of literature. Gen Hosp Psychiatry. 2013;35(1):102e3-6.
12. Kailasam VK, Chima V, Nnamdi U, Sharma K, Shah K. Risperidone-induced reversible neutropenia. Neuropsychiatr Dis Treat. 2017;13:1975-1977.
13. Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol. 2000;22(1):62-65.
14. Watts RG, Emanuel PD, Zuckerman KS, Howard TH. Valproic acid-induced cytopenias: evidence for a dose-related suppression of hematopoiesis. J Pediatr. 1990;117(3):495-499.
15. Storch DD. Severe leukopenia with sodium valproate. J Am Acad Child Adolesc Psychiatry. 2000;39(10):1208-1209.
16. https://www.uptodate.com/contents/management-of-the-adult-with-non-chemotherapy-induced-neutropenia
17. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015;33(28):3199-3212.
18. Mhaskar R, Clark OAC, Lyman G, Botrel TEA, Paladini LM, Djulbegovic B. Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database Syst Rev. 2014;(10).
19. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med. 2007;146(9):657-665.
20. Andrès E, Maloisel F, Kurtz JE, Kaltenbach G, Alt M, Weber JC, et al. Modern management of non-chemotherapy drug-induced agranulocytosis: a monocentric cohort study of 90 cases and review of the literature. Eur J Intern Med. 2002;13(5):324-328.
21. Andrès E, Lorenzo Villalba N, Zulfiqar AA, Serraj K, Mourot-Cottet R, Gottenberg JE. State of art of idiosyncratic drug-induced neutropenia or agranulocytosis, with a focus on biotherapies. J Clin Med. 2019;8(9):1351.
22. https://www.moh.gov.sg/docs/librariesprovider4/guidelines/mohcpg_bipolar-disorder_booklet.pdf
23. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, et al. Canadian network for mood and anxiety treatments (CANMAT) and international society for bipolar disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2): 97-170.