Two-Year Follow-Up of a Patient With Successful Continuation of Clozapine Treatment Despite Morning Pseudoneutropenia

Abstract

Sir: Agranulocytosis occurs in 1% to 2% of patients treated with clozapine. Thus, if neutropenia (absolute neutrophil count [ANC] of < 1500/µL) occurs during clozapine treatment, physicians generally interrupt the drug treatment and do not reintroduce it. Lithium and granulocyte colony-stimulating factor may be used to reverse clozapine-induced granulocytopenia. 1 We have previously reported the case of a patient who was able to continue clozapine treatment despite developing "morning pseudoneutropenia" (MPN). 2 In this report, we describe the course of the clozapine treatment over the following 24 months.Case report. In January 2002, clozapine treatment was administered to Mr. A, a 44-year-old white man with DSM-IV paranoid schizophrenia who had previously shown resistance to various other antipsychotics. Prior to treatment, the patient's total white blood cell count (WBC) and ANC were 7100/µL (normal range, 4500-11,000/µL) and 5300/µL, respectively. His clozapine dose was gradually increased to 200 mg/day, leading to a satisfactory improvement in symptoms. Concomitant medication consisted of valproic acid (2000 mg/day).After 27 weeks of clozapine treatment, the patient's WBC and ANC had declined to 4100/µL and 1300/µL, respectively. However, a subsequent physical examination, Mr. A's medical history, and baseline laboratory investigation did not indicate that chronic or acute inflammation or infection, or autoimmunologic or hematologic disease, had developed. After the first blood sample was taken at 8 a.m., a second blood sample was taken at 2 p.m. later that day, and the patient's WBC and ANC were in the normal range (5500/µL and 2200/µL, respectively).Clozapine treatment was continued with a strict hematologic monitoring program: blood tests were performed at 8 a.m. and at 2 p.m. twice a week. During the following 3 weeks, Mr. A's ANCs were persistently between 1200/µL and 1900/µL at 8 a.m. (corresponding WBCs: 4100-4700/µL) and between 2200/µL and 2700/µL at 2 p.m. (corresponding WBCs: 5400-5800/µL).Thereafter, monthly blood tests were systematically performed at 2 p.m. During the following 24 months, the patient's ANCs remained within the normal range. Clozapine treatment was thus continued, and the patient has since shown a great improvement in his social function.Morning pseudoneutropenia is known to occur during clozapine treatment. 2,3 However, due to short follow-up periods in previous reports, the duration and severity of this phenomenon were unknown. On the basis of this and other case reports, 2,3 we hypothesize that MPN is a transient and harmless type of neutropenia rather than an early sign of incipient agranulocytosis.

Haematological toxicity of drugs used in psychiatry

“…In one such patient the leucocyte results were 2.9-4.2 L À9 in the morning and 3.6-7.1 L À9 in the afternoon, with granulocytes 0.8-1.4 L À9 and 2.9-5.5 L À9 , respectively (Ahokas and Elonen, 1999). Circadian variations in the number of circulating neutrophils have also been described in several non-Jewish Caucasians (Esposito et al, 2004(Esposito et al, , 2005a. Clozapine may thus be withdrawn unnecessarily unless account is taken of this phenomenon.…”

Nonchemotherapy Drug-Induced Neutropenia and Agranulocytosis

“…20 It is unclear why MPN occurs with clozapine treatment, but one thought is that clozapine may make the circadian differences in circulating neutrophils more pronounced. 24 Providers may want to have the blood drawn in midmorning or afternoon to avoid discontinuing clozapine because of this effect. The addition of lithium has been used in both pediatric and adult patients with schizophrenia having clozapine-induced neutropenia.…”

Genetics of Antipsychotic-induced Side Effects and Agranulocytosis

“…Environmental factors also must be considered but as yet have not been systematically evaluated. For example, there is evidence that fluctuations in circadian rhythm impact the number of circulating neutrophils in patients [37,81]. Along similar lines, it has been demonstrated that moderate exercise increases white blood cell count [37], and typical schizophrenia patients usually have lower interest in exercise.…”