Clozapine-induced bicytopenia: An unusual side effect.

Agranulocytosis is a rare documented side effect of clozapine which can be associated with grave consequences. When it is associated with other blood dyscrasia, prognosis worsens further. In literature, there are very few cases of pancytopenia and bicytopenia caused by clozapine. We present a case of bicytopenia (reduced white and red blood cells' counts) caused by clozapine within a month of therapy and complicated by a Klebsiella pneumoniae infection. Patient improved in 3 weeks after stopping clozapine along with medical management in the Intensive Care Unit. Such side effects, though rare, can be life threatening and warrants intermittent complete blood monitoring besides regular assessment of granulocytes and neutrophils when any patient is prescribed clozapine.

Introduction

Clozapine is an atypical antipsychotic agent used for treating patients with resistant type of schizophrenia [1] and many other psychotic spectrum illnesses. Among various side effects, agranulocytosis is a rare (prevalence - 0.8%), but life-threatening adverse drug reaction that can occur in some patients. Agranulocytosis is considered when the granulocyte count is < 0.5 × 103/μl, whereas leukopenia means a total leukocyte count (TLC) of < 3.5 × 103/μl. The etiology can be variable including immune mediated, because of idiosyncratic reactions (type B) or due to suppression of hematopoietic precursors with prolonged administration of the drug.[2] Agranulocytosis makes patient susceptible to other infections because of impairment in the immunity. Literature shows only a few case reports of clozapine-induced pancytopenia [34] and still less literature is available for the occurrence of bicytopenia (reduced red blood cells [RBCs] and white blood cells [WBC]) due to clozapine. Pancytopenia is a medical condition in which there is a reduction in platelets and the number of WBCs and RBCs. If any two parameters (e.g., platelets and RBCs or WBC and RBCs) from complete blood count (CBC) are low, the condition can be termed as “bicytopenia.” The clinical and diagnostic approach to bicytopenia is the same as that for pancytopenia. This is a rare case report of bicytopenia caused by clozapine.

Case Report

A 56-year-old male presented to a medical emergency department with complaints of high-grade fever, altered behavior in the form of irrelevant talk, agitation, and irritability with fluctuating orientation for 2 days.

The patient was a known case of undifferentiated schizophrenia as per International Classification of Diseases, 10th edition since past 24 years and was on regular treatment with good compliance since the start of treatment. Initial symptoms of the patient included suspicion against family members that they will harm him, muttering and gesticulating to self, aggressive and abusive behavior, reduced sleep, and disinhibited behavior for which he was treated with electroconvulsive therapy and psychotropic medication during initial period. The patient improved in a few weeks and continued the treatment as advised by the psychiatrist. The patient had aggravation of symptoms while on medication multiple times mostly without any precipitating factors during the course of illness. Since 24 years, the patient had been prescribed various antipsychotic medications including trifluperazine, risperidone, and olanzapine in adequate doses and for adequate duration. Quetiapine was prescribed in low doses for agitation whenever required as per the response. In spite of being compliant to the treatment, the patient never improved to a premorbid level and some residual symptoms would always remain. The patient had been admitted under psychiatrist's care for three times due to aggravation of symptoms despite being compliant in the past few years before he was considered to be a case of resistant schizophrenia and prescribed tablet clozapine with normal baseline CBC and weekly counts were advised. Dose was gradually increased to reach up to 200 mg in 2 weeks along with continuation of risperidone 4 mg in divided doses. Patient showed partial improvement in symptoms after 2 weeks of treatment and improvement was increasing slowly.

Within 30 days of starting clozapine, the patient presented to the casualty with above symptoms suggestive of some organicity. The patient also had urinary complaints (urgency and frequency). Neuroimaging revealed no abnormality, but urine examination showed plenty of pus cells. Urine and blood culture revealed infection with Klebsiella pneumonia with signs suggestive of cystitis on ultrasonography. His serum potassium levels were low (2.57 mEq/L) with deranged kidney and liver functions. Patients' CBC revealed low hemoglobin of 7.6 g% and TLC of 400/mm3 (differential count could not be done due to low leukocyte count) with 3.47 mil/ul RBCs. His platelet count was normal (3.42 lakh/mm3). Bone marrow biopsy was suggestive of “depressed granulopoiesis and erythropoiesis with hypoplastic anemia.” Patient was negative for antinuclear antibodies and his cardiac functioning in echocardiography was within normal limits. There were no abnormalities in other blood investigations. The patient was treated in the Intensive Care Unit (ICU) with antibiotic drugs, adequate hydration, supportive treatment, and other measures. Clozapine was stopped immediately, risperidone dose was increased to 6 mg (divided doses), and aripiprazole was added in 5 mg dose that was later increased. Patients' blood investigation charting was done, and there was improving trend in blood counts. Slowly patients' hemoglobin increased to 9.4 g/dl at the end of 3 weeks. TLC found increased in subsequent testing, and at the end of 3 weeks, it was 6900/mm3 with absolute neutrophil count (ANC) 5796/mm3. RBC count increased to 4.3 mil/ul at the time of discharge. Serum potassium level became normal within few days of admission. There was no growth on urine and blood culture on repeat testing.

When the patient was discharged, dose of aripiprazole was increased to 30 mg in the next few days along with risperidone 6 mg. The patient showed aggravation of symptoms within a week of stopping clozapine but again reported improvement after increasing the dose of aripiprazole.

Discussion

Though rare, clozapine has been known to cause hematological side effects such as agranulocytosis, neutropenia, leukocytosis, eosinophilia, and thrombocytopenia. Literature shows that around 2.7% of the patients receiving clozapine can develop neutropenia, with < 1% developing agranulocytosis. About 50%–80% of the cases occur within 18 weeks of starting the drug.[5] This patient developed hematological side effects within 30 days of starting clozapine. It is recommended that baseline TLC and ANC should be performed before prescribing clozapine to the patient and it should be repeated later every week for the first 6 months, fortnightly for the next 6 months, and monthly thereafter as per the guidelines. Literature shows different reports in the past few years demonstrating the fact that agranulocytosis and neutropenia can be prevented with strict hematologic surveillance.[6] The patient in this case report had normal WBC (7400/mm3) and ANC (4900/mm3) count at baseline initially and was advised follow-up and blood counts weekly. The differential count in between was normal (TLC 5600/mm3 and ANC 3200/mm3) and the patient was due for follow-up. Clozapine is categorized under schedule “H” drug in India as per the notification by the Ministry of Health and Family Welfare (Department of Health) in 2006,[7] and it is easy to get clozapine even without blood counts. Many patients with resistant schizophrenia show a good response to clozapine; this patient also showed improvement in symptoms after around 2 weeks of treatment with no major side effects except mild sedation and salivation. The patient did not develop any symptom suggestive of low WBC count during a month of treatment until he presented to the medical emergency department for fever and delirium. Low granulocytes increase the risk of infection due to reduced immunity which might be the reason for developing K. pneumonia infection in this patient. It is a well-known fact that this infection usually occurs in patients who are hospitalized (especially in the ICU), in immunocompromised conditions such as alcoholism and diabetes mellitus, on antimicrobial (antibiotic) therapy, with the use of invasive medical procedures for prolonged period, practice of inadequate infection control, severe medical or surgical illness, and after major surgical procedures.

There are many case reports of agranulocytosis due to clozapine improving within few days/weeks after stopping the drug. Very few case reports are available about pancytopenia caused by clozapine improving subsequently with stoppage of drug. We found reduced RBCs and WBCs but normal platelet count. Literature also shows very few studies reporting incidence of thrombocytopenia associated with clozapine.[89] This patient showed improvement after stopping clozapine in the next 3 weeks. Usually, psychiatrists tend to monitor WBCs and ANC (as per the guidelines) when they start clozapine to any patient, but in some patients, intermittent assessment of other blood cells is also necessary to detect or prevent serious side effects such as pancytopenia or bicytopenia.

After starting clozapine if the WBC count subsequently drops to < 3000/mm3 or the neutrophil count falls to < 1500/mm3, clozapine needs to be stopped.[6] In this patient, bicytopenia was identified after 30 days of clozapine therapy, and no blood counts were done during this period except normal differential count once (in 30 days) so such monitoring could not be done.

Usually, the recovery of blood dyscrasia occurs after 4 weeks of stopping clozapine.[4] This patient recovered completely from clozapine-induced bicytopenia within 3-week period. It is important to monitor blood counts in each patient receiving clozapine at baseline as well as subsequently on follow-up as per the guidelines to prevent any serious consequences.

Conclusion

Clozapine-induced bicytopenia, though extremely rare, can be life threatening and it is important to monitor CBC periodically besides regular assessment of granulocytes and neutrophil count for early detection of the condition. This is a rare case of clozapine-induced bicytopenia which developed within a month of starting clozapine and complicated by K. pneumonia infection (systemic). Patient improved within 3 weeks of stopping clozapine along with medical line of management (antibiotics, supportive treatment, and ICU care).

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Conflicts of interest

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