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Repeated Episodes of Neutropenia Triggered by Mirtazapine

TO THE EDITOR: Severe neutropenia, defined as < 0.5 x 10⁹/L mature neutrophil cells, is a potentially life-threatening side effect of mirtazapine, occurring with a risk of up to 1 in 1,000 instances.¹ Several reports of mirtazapine-induced neutropenia can be found in the medical literature.^2–7 We report a patient who developed neutropenia in association with a standard dose of mirtazapine (15 mg) after 2 separate trials. The close temporal association between the administration of mirtazapine and the lowering of her neutrophil count strongly suggests that the neutropenia is related to the mirtazapine.

Case Report
A 29-year-old woman with a 5-year history of chronic unexplained abdominal pain associated with persistent nausea and emesis was admitted to the hospital for symptom-control. She had run out of her supply of odansetron and morphine. She had a medical history of diabetes mellitus Type 1 on insulin pump, anemia of chronic disease (baseline hemoglobin 10–12), gastroesophageal reflux disease with severe esophagitis, and mononeuropathy with left foot drop. She had no obvious past history of hematologic disorders. A thorough medical evaluation in the hospital revealed mildly abnormal gastric motility, negative porphyrins, anti-gliadin antibodies; ANA studies were performed; there was a negative abdominal CT scan. Intravenous hydration, antiemetics, and narcotics were given, with steady improvement in symptoms. Gradually, the patient was able to initiate a gastroparesis diet. She reported significant demoralization and hopelessness in the setting of her medical illness, which prompted a psychiatric consultation.

Given her complaints of nausea and insomnia, a trial of sublingual mirtazapine was recommended, with a starting dose of 15 mg. Careful review of her laboratory studies indicates that her hemoglobin (HGB) was 13 on admission; WBC count: 4; absolute neutrophil count (ANC): 3.59 (normal); platelet count: 220,000 (normal). Previous complete blood counts (CBCs) dating back to December of 2006 were essentially normal.

One day before initiation of mirtazapine, her HGB had fallen to 10.8, possibly due to hydration; her white-cell count was still 6,000; with an ANC at 4.55, and a platelet count of 188,000. After her first dose of mirtazapine, her hemoglobin was 11.6, with a WBC of 3,000; ANC was down to 2.18; and platelets were 208,000. After two doses of mirtazapine, her hemoglobin was stable at 11.9, but WBC was 2.9, with an ANC that had now fallen further, to 0.92. After three doses of mirtazapine, her HGB was 12, WBC: 2.7, ANC: 0.81, and platelet count: 203,000. After her fourth dose of mirtazapine, her HGB was 11; WBC: 3.6; ANC: 0.53; and platelet count: 192,000.

Immunoglobulin studies, vitamin B₁₂, folate, immunofixation, EBV antibodies, HHV-6, CMV antigens, and ferritin studies were within normal limits. In the absence of any other mechanism after her unremarkable laboratory work-up, hematology staff recommended the discontinuation of mirtazapine. The ANC increased to 630 1 day after discontinuation of mirtazapine.

The hematology staff noted the close temporal relationship between the mirtazapine and the lowering of her ANC, strongly suspecting that the neutropenia was related to the mirtazapine. A careful review of the patient’s medical history revealed an earlier trial of mirtazapine of 1-day duration a month before admission. Review of her laboratory studies during that time demonstrated a dramatic fall in her ANC from 5,000 down to 1,620 after a single dose of mirtazapine. Mirtazapine was stopped because of the suspicion of a link. The recognition that the patient had once again experienced neutropenia when rechallenged with mirtazapine led further credence to the causal association.

To our knowledge, this case is singular in being effectively a single-case experimental design. The re-exposure aspect of the case is unique. The temporal association between administration of mirtazapine and lowering of neutrophil count strongly suggests that the neutropenia is related to the mirtazapine. Given the rapid onset of neutropenia, the suspicion of an underlying bone marrow disorder was low. This patient had several chronic medical disorders, including diabetes mellitus and anemia of chronic disease; however, neither of these has been established as a risk factor for neutropenia. Although erythromycin, promethazine, pantoprazole, and metoclopramide have been associated with blood dyscrasias, these medications were longstanding therapies used by the patient before her hospitalization, and were unchanged during her stay. Mirtazapine was the only new agent introduced. Only mirtazapine therapy was discontinued, and neutrophil count increased back to normal values several days after cessation. Furthermore, this result was repeated on both occasions that the patient was tried on mirtazapine. The sequence of these events supports our observation that rapid-but-reversible neutropenia was associated with mirtazapine therapy at a standard nightly dose of 15 mg.

REFERENCES

1. Hartmann PM: Mirtazapine: a newer antidepressant. Am Fam Physician 1999; 59:159–161[Medline]
2. Ahmed A: Neutropenia associated with mirtazapine use: is a drop in the neutrophil count in symptomatic older adults a cause for concern? J Am Geriatr Soc 2002; 50:1461–1463[Medline]
3. Anghelescu I, Klawe C, Dahmen N: Venlafaxine in a patient with idiopathic leukopenia and mirtazapine-induced severe neutropenia (letter). J Clin Psychiatry 2002; 63:838[Medline]
4. Davis J, Barkin RL: Clinical pharmacology of mirtazapine: revisited (comment). Am Fam Physician 1999; 60:1101[Medline]
5. Kasper S, Praschak-Rieder N, Tauscher J, et al: A risk-benefit assessment of mirtazapine in the treatment of depression. Drug Saf 1997; 17:251–264[Medline]
6. Montgomery SA: Safety of mirtazapine: a review. Int Clin Psychopharmacol 1995; 10:(suppl 4):37-45
7. Ozcanli T, Unsalver B, Ozdemir S, et al: Sertraline- and mirtazapine-induced severe neutropenia (letter). Am J Psychiatry 2005; 162:1386[Free Full Text]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by Civalier, K. A. Articles by Agrwal, N. Search for Related Content PubMed Citation Articles by Civalier, K. A. Articles by Agrwal, N. Depression Syndromes Secondary to General Medical Disorders Antidepressants

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