Neutropenia Associated with Mirtazapine Use: Is a Drop in the Neutrophil Count in a symptomatic Older Adults a Cause for Concern?

To the Editor: During premarketing trials, three patients taking mirtazapine (Remeron) developed neutropenia/agranulocytosis, 1 but there is no such report in the medical literature. We report a case of a 93-year-old woman whose absolute neutrophil count (ANC) dropped on mirtazapine and then returned to normal after discontinuation of the drug. Drugs are the second-most-common cause of isolated neutropenia.2 Although selective serotonin-reuptake inhibitor antidepressants are commonly prescribed in older adults,3 neutropenia associated with these drugs is rare, and there is only one such report in the literature.4 Alternatively, tricyclic5–7 and tetracyclic8–10 antidepressants are known to be associated with neutropenia and agranulocytosis. The incidence of agranulocytosis/severe neutropenia (ANC <500/mm3) associated with mirtazapine, a tetracyclic antidepressant, was 11/10,000 during premarketing trials,1 but it is unknown how many patients in those trials had ANC between 501 and 1,800/mm3. Unpublished data suggest that, until 1999, there were six cases of neutropenia (ANC unknown) associated with mirtazapine use.11 A 93-year-old woman presented to a university geriatrics clinic for dementia evaluation. After a complete dementia workup, a diagnosis of Alzheimer's disease was made, and she was started on donepezil. Although she had a sad affect, her Geriatric Depression Scale score was normal, and no antidepressant was started. Six months later, the daughter reported continued depressed mood, and antidepressant therapy with mirtazapine 15 mg/day was started. Her total white blood cell (WBC) count before initiation of mirtazapine therapy was 7,800/mm3 with 41% neutrophil (ANC = 3,198/mm3). Five months later, although her appetite improved, she remained depressed, and her mirtazapine dose was increased to 30 mg/day. At that time, her total WBC count was 8,900/mm3, with 38% neutrophil (ANC = 3,382/mm3). Three months later, her WBC count was 8,020/mm3, with 34% neutrophil (ANC = 2,727/mm3) (see Figure 1). She did not receive any new medications, nor were the dosages of any other drugs increased during this time. She was asymptomatic. Her mirtazapine was discontinued, and therapy with sertraline 50 mg/day orally was started. A follow-up cell count 2 months after discontinuation of mirtazapine revealed a total WBC count of 9,240/mm3, with 39% neutrophil (ANC = 3,604/mm3). Absolute neutrophil count in relation to the use of mirtazapine. Like other tetracyclic antidepressants,8–10 mirtazapine is known to cause neutropenia/agranulocytosis.1,11 Neutropenia is defined by an ANC less than 1,800/mm3.12 The ANC reported in this case did not meet that definition. This is most likely because of our close monitoring and early detection of her ANC drop. Nevertheless, we chose to discontinue mirtazapine therapy, because we were concerned about the possibility of a further drop in ANC with subsequent full-blown neutropenia/agranulocytosis in this older patient. The patient's WBC counts and ANC before and after discontinuation of the therapy were higher than those reported when she was on mirtazapine 30 mg/day. Although a causal association cannot be established, an association was suggested by the restoration of her cell counts to the baseline when mirtazapine alone was discontinued. The onset of neutropenia in our case was later in the course of therapy than that observed during the premarketing trials (9–61 days) and was only noticed after the dose of mirtazapine was increased. This late onset of action, especially after an increase in dosage, suggests a possible dose-dependent inhibition of granulopoiesis by mirtazapine.13–15 An alternate explanation of her drop in neutrophil count would be a physiological variation, with the trough coinciding with her mirtazapine dose increase. Although no recommendations can be made based on this case report, especially because the patient did not develop full-blown neutropenia, physicians prescribing mirtazapine need to be aware of this association. In the premarketing clinical trials (N = 2,796), three patients treated with mirtazapine developed agranulocytosis (ANC <500/mm3), and discontinuation of the drug was associated with complete recovery.1 The manufacturer of mirtazapine recommends discontinuation of the drug “if a patient develops a sore throat, fever, stomatitis or other signs of infection, along with a low WBC count.”1 However, in older adults, it might be prudent to discontinue therapy when a drop in ANC is noted and before any symptoms or signs of infection develop. Physicians should monitor total and differential WBC counts of patients receiving mirtazapine at least several times during the first year of the therapy and especially after any dose increase. They should also discuss the risk of neutropenia with their patients and advise them to report any fever, chills, cold- and flu-like symptoms, sore throat, muscle ache, ulceration in the mouth, or other signs of infections. Discontinuation of the drug should result in normalization of the cell counts.