Abstract
Combinations of psychotropic medications are prescribed frequently for patients whose illnesses prove resistant to single agents. When adverse events occur in such situations, particularly when using the newer agents, determining which medication or combination is responsible is difficult.
We report an episode of neutropenia in such a patient, in which the temporal sequence strongly suggests that nefazodone was the cause.
The patient, a 42-year-old woman, had a 20-year history of bipolar affective disorder, with a rapid-cycling, treatment-resistant pattern emerging despite trials of all conventional mood-stabilisers. Clozapine was added to her sodium valproate (2500 mg daily) in June 1998, and, at a dose of 325 mg daily, prevented further episodes of mania. Because of her continued and severely disabling depressions, nefazadone was commenced (other antidepressants having proven ineffective) on 15 October 1999. The dose was gradually increased over 3 weeks to a maximum of 200 mg twice daily. Within a week of reaching this dose her neutrophil count, having previously always been within the normal range, decreased to 1.8 × 109/L. The nefazodone was continued, but the white blood count monitored on alternate days. The neutrophil count remained in the range of 1.7–2.3 × 109/L (with one exception of 2.9 × 109/L), over the next month, with 50% of the results equal to or below 2.0 × 109/L. At this point, the nefazodone was discontinued due to concern at the persisting low neutrophil count, unacceptable side-effects and lack of response. Within 1 week of the discontinuation of nefazodone her neutrophil count rose to 4.6 × 109/L and has continued in the range of 2.5–5.3 × 109/L since.
Neutropenia is not a recognised adverse effect of nefazodone. The manufacturers do not report any cases, and the World Health Organization database reports three cases, only one of which is well-documented. A search of Embase/Excerpta Medica found one report, that of Fogelson [1], who reported a similar case with a rapid onset of leukopenia after starting nefazodone which remitted within a short time of the drug's discontinuation.
Clozapine can cause neutropenia. However, it is unlikely that this occurred in a transitory fashion after 16 months on clozapine, during which time the patient had not had any episodes of leucopenia. Nefazodone can cause a rise in the serum level of clozapine [2], but the leucopenic effect of clozapine is not dose-related [3], and the patient's serum level of clozapine remained stable during this time.
Sodium valproate is known to cause leucopenia [4]. However, given that the patient had been stable on this medication for some years without any adverse effects, it seems unlikely that this transient event was caused by valproate. The serum valproate level remained stable throughout this time.
Because of the patient's lack of response to the medication, and its unacceptable side-effects, as well as the ethical issues, she was not rechallenged with nefazodone. However, the temporal sequence, with the return of the neutrophil count to normal after the discontinuation of the nefazodone, must raise concern that this drug may have been responsible.