The authors’ observations
For Mr. G, both bupropion and sertraline appear to have caused neutropenia on separate occasions.
To our knowledge, bupropion-induced leukopenia or neutropenia have not been reported in the literature. Neutropenia—a rare adverse effect of antidepressants2—and leukopenia were seen during bupropion’s pre-marketing trials but were not definitely attributed to the drug.1 According to pre- and post-marketing data, leukopenia was “infrequently” reported among 5,100 subjects who received bupropion.3
To our knowledge, sertraline-induced neutropenia has not been reported in nongeriatric patients, although sertraline-induced neutropenia4 and agranulocytosis5 have been reported in patients age >65. The Committee on Safety of Medicine in the United Kingdom has received 2 other reports of neutropenia and 1 report of leukopenia with sertraline.5
In one clinical trial, 2 of 1,304 patients taking unknown dosages of sertraline had low neutrophils (
Medication is the second most common cause of acquired neutropenia, with infection being most common.6 By definition, drug-induced neutropenia occurs within 4 weeks after starting the drug and usually resolves within 30 days after stopping it.
Neutropenia is an idiosyncratic reaction unrelated to pharmacologic action. Although overall neutropenia incidence is unknown, reported incidence of the rare, more severe agranulocytosis ranges from approximately 1 to 10 cases per million people annually, and medications have been implicated in 70% of these cases.6 Conversely, only 2 of 97 incidental neutropenia cases studied by Lima et al7 were medication-induced.
Drug-induced neutropenia can result from immune-mediated destruction of neutrophils by circulating antibodies or from direct toxic effects upon marrow granulocyte precursors. Whereas immune-mediated onset is acute and explosive, toxic effect is insidious (months to years) and asymptomatic.8 Clozapine is thought to deliver a direct toxic effect, whereas the thyroid-regulating drug propylthiouracil generates anti-neutrophil antibodies.9
Mr. G’s acute onset (within 5 to 16 days of starting bupropion or sertraline) and prompt return of neutropenia after stopping lithium suggest acute immune-mediated circulating neutrophil destruction.
Treating leukopenia
After 4 failed or intolerable antidepressant trials, lithium augmentation seemed reasonable and ultimately improved Mr. G’s neutrophil count and his mood.
Lithium has helped resolve clozapine-induced neutropenia in case reports.10-12 Well-controlled studies, however, have followed only patients with antineoplastic, drug-induced neutropenia.1
By acting on cyclic nucleotides, lithium prompts colony-stimulating factor production, which in turn stimulates neutrophil production by pluripotent stem cells. As with Mr. G, patients reach neutrophilia 3 to 7 days after starting lithium.
If the patient cannot tolerate lithium, try switching antidepressants or using growth factors to increase neutrophils.
Switching antidepressants.The SSRIs escitalopram or paroxetine, or the SNRI duloxetine are effective and do not necessarily cause neutropenia. Start at below-normal dosages to gauge tolerability, then titrate to normal dosages. Avoid tricyclics, which pose a higher risk of neutropenia than other antidepressant classes.
Case reports13,14 associate fluoxetine and mirtazapine with neutropenia. The patient who received mirtazapine, 30 mg/d, later responded well to sertraline, 50 mg/d.13
If the new antidepressant is ineffective, consider adding the mood-stabilizing anticonvulsant lamotrigine, 12.5 mg/d. Increase lamotrigine to 25 mg/d after 1 week, then titrate by 25 mg weekly to 100 to 400 mg/d depending on efficacy and tolerability.
Using growth factors.Although their efficacy is not proven, growth factors are minimally toxic and might have helped Mr. G. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor resolved neutropenia in uncontrolled studies, but results of one randomized controlled trial were equivocal.8
TESTING: CT findings
Approximately 2 months after admission—shortly after a blood draw shows normal WBC and neutrophils—Mr. G complains of dizziness. He says he accidentally hit his head against a side table.
We order a full neurologic workup to check for traumatic brain injury or brain damage caused by long-term alcohol abuse:
- Head CT shows evidence of previous cerebrovascular infarcts in the bilateral frontal and cerebellar lobes and basal ganglia.
- MRI shows atrophied mammillary bodies, fornix, and corpus callosum.
- Magnetic resonance angiography reveals small cerebral vessel disease.
FOLLOW-UP: Awaiting discharge
After 3 months of continuous hospitalization, Mr. G has become euthymic and nonsuicidal, though at times oversensitive and combative. We transfer him to an assisted-living center and continue sertraline, 150 mg/d; phenytoin, 300 mg/d; phenobarbital, 30 mg bid; lithium, 300 mg/d; and trazodone, 50 mg at night as needed for insomnia.