Case description

Mr G, a 62-year-old married man, retired electrician by occupation was brought by his family members with complaints of hearing of voices over the past 10 years. There was no relevant medical history or family history of mental illness. Detailed exploration of history revealed an illness of insidious onset with a continuous and progressive course which was precipitated by interpersonal problems with office colleagues. Following which initially, the patient started to harbour strong fixed false beliefs that his colleagues wanted to defame him with subsequent anger-outbursts, agitation and suspiciousness towards them. Later on, after few months, he even started to hear voices of his office colleagues in clear consciousness discussing him and commenting on his actions using derogatory language. Due to these events, there was significant socio-occupational dysfunction. He was treated with risperidone (2–4 mg/day) with good compliance for a period of 6 months with which there was about 60% improvement but later because of non-compliance and restarting of risperidone he did not show any response. Detailed general physical and systemic examination did not reveal any abnormality and mental status examination was suggestive of auditory hallucinations—third person discussing type, delusions of persecution and reference, low mood and suicidal ideations secondary to psychotic symptoms with absence of insight and intact cognitive functions (Mini mental state examination—28/30). A diagnosis of paranoid schizophrenia as per ICD-10 was considered. After all essential routine haematological (complete blood count) and biochemical investigations (serum electrolytes, liver function tests, lipid profile, renal function tests, serum vitamin B12 and folate), all of which came out to be normal, he was started with Olanzapine 5 mg which was gradually increased to 15 mg over a period of 3 weeks (5 mg increment in dose per week). There was reduction in psychotic symptoms by 40%–50% but on subsequent follow-ups, after 6 weeks of starting Olanzapine, the patient complained of excessive fatigability. On repeat investigations, there was evidence of total leucocyte count of 2600/cumm (baseline—9400/cumm) and total platelet count of 45 000/cumm (baseline—130 000/cumm) without any evidence/history of fever and symptoms suggestive of any local or systemic infection and intake of any other medications. Haematology consultation and detailed autoimmune workup to rule out other possible aetiologies (hepatosplenomegaly, autoimmune antinuclear antibodies and antineutrophil cytoplasmic antibodies) were found to be negative. Following this, a possibility of Olanzapine induced leucopaenia and thrombocytopaenia was considered and the drug was stopped. The patient was admitted for inpatient serial monitoring of haematological parameters and after stopping of Olanzapine, serial monitoring revealed an increase in total leucocyte count (8900/cumm) and total platelet count back to normal range (156 000/cumm) within a week. Later on, he was started on aripiprazole 2.5 mg with a very slow hiking of dosage (2.5 mg/fortnightly) along with monitoring of haematological parameters and psychopathology. At 10 mg of aripiprazole after a period of 30 days, the patient showed significant improvement in mood and psychotic symptoms by around 75% and his haematological parameters continued to remain stable over the next 4-month follow-up period. The prognosis of the patient was good and there was no relapse of any haematological abnormalities.

Discussion

In the index elderly subject, olanzapine-associated leucopaenia and thrombocytopaenia were detected just after 6 weeks of starting Olanzapine at a dosage of 15 mg/day. After ruling out all possible causes of these haematological abnormalities, olanzapine was considered to have induced these adverse effects. Leucopaenia and thrombocytopaenia have been rarely reported with olanzapine and the exact incidence rate is currently unavailable. In the literature search, seven published case reports on olanzapine-induced blood dyscrasias have been reported with elderly subjects (details mentioned in table 1). Pancytopaenia and neutropaenia were also reported with thrombocytopaenia in two of these case reports with elderly subjects. Rechallenge with the same drug was not possible due to ethical reasons.

It was also seen that olanzapine-induced haematological abnormalities can be seen at any time of treatment duration ranging from the first day13 to 204 days.29 The index case developed leucopaenia and neutropaenia after around 42 days (6 weeks) of starting of olanzapine. Of the seven case reports, while there was reported fatality in only in one case15, the others improved with stoppage of olanzapine (though one required granulocyte colony stimulating factor (G-CSF) additionally13). Similarly, stoppage of olanzapine led to improvement in haematological parameters within a week, which further ascertains that olanzapine was the definite agent for inducing leucopaenia and thrombocytopaenia in the index case. The Naranjo probability score30 was 9 indicating a definite association of leucopaenia and thrombocytopaenia with olanzapine in the index case.

Though the exact mechanism of action of olanzapine induced neutropaenia and leucopaenia is not known, considering it’s chemical structure and pharmacological receptor profile are quite similar to clozapine, those mechanisms proposed for clozapine induced haematological abnormalities can be postulated for olanzapine too. Some of these proposed mechanisms are: (1) olanzapine can modulate levels of the G-CSF and can cause subsequent transient granulocytopaenia like clozapine31 and (2) possibly olanzapine use can also lead to formation of nitrenium cations catalysed by Flavin containing monoxenage-3 system of leucocytes like clozapine.32 However, both of these hypotheses are not yet proven.

It has been suggested to screen patients as high and low risk for developing olanzapine-induced haematological abnormalities (ie, high risk includes previous history of haematological diseases, family history of blood dyscarcias and any previous history of drug-induced granulocytopaenia).26 We further suggest that being an elder be included under high-risk screening for olanzapine-induced haematological abnormalities and a thorough meticulous complete blood count once a month within the first 3 months33 be carried out so as to detect any haematological abnormality at the earliest time possible.

The index case adds to the extremely limited literature on olanzapine-induced leucopaenia and thrombocytopaenia in elderly subjects and suggests that whenever an elderly patient receiving olanzapine has objective evidence of any blood dyscrasias, olanzapine must be suspected and stoppage should be considered as early as possible to avoid deleterious results.