Severe Psychotic Disorder and Agranulocytosis – A Therapeutic Dilemma

 

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Schizophrenia is a severe mental disorder leading to chronic disability, poor social functioning and an increased risk of harm to self [6] and others [8]. The most important treatment is pharmacotherapy with different classes of antipsychotics. However, these substances bear considerable risks of side effects. The most dangerous is agranulocytosis (absolute neutrophil count ANC<100/μL) with mortality rates between 5 and 10%. All antipsychotics can cause agranulocytosis, the highest risk is known for clozapine [4]. For all neuroleptics, the use is restricted in case of mild neutropenia (ANC<1 500/μL) and contraindicated in case of moderate (ANC<1 000/μL) and severe neutropenia (ANC<500/μL). Several reports describe continuation of clozapine treatment despite neutropenia with co-administration of granulopoesis-stimulating factors [3] or rechallenge with clozapine following neutropenia during previous therapy [2]. However, administration or continuation of neuroleptics in patients with continuous severe neutropenia has never been reported so far. We describe a case in which an urgent need for antipsychotic therapy was obvious against the background of a critical clinical situation with pre-existing severe neutropenia.

In January 2007, a 39-year-old man was referred to our hospital after an attempted suicide. He had wounded himself in a forest with a carpet cutter at both back of the feet and the left forearm imitating the cicatrices of Jesus Christ. A chronic paranoid schizophrenia had been diagnosed about three years before. In 2002, he quit his job, was unemployed from then on and lived with his parents. Neutropenia was known since 2004 with a leukocyte count of about 2 500/μL. Recurrent hematological diagnostic investigations including bone marrow histology, immunophenotyping and cytogenetic analysis did not reveal any hematological disease. No further decline occurred under treatment with haloperidol but with amisulpride and risperidone. Having experienced severe extrapyramidal side effects under haloperidol, finally the patient had been discharged without neuroleptic treatment after his last admission.

Actually, he experienced auditory hallucinations and religious delusions. We administered lorazepam to suppress suicidal ideas. Initially, no neuroleptics were given because of the known neutropenia. The lowest spontaneous leukocyte count was 1 400/μL, the lowest neutrophil count 234/μL, thus meeting the clinical criteria of agranulocytosis. Two administrations of granulocyte-colony stimulating factor G-CSF yielded high but not sustained leukocyte counts indicating an intact bone marrow. In the meantime, the patient wounded himself again and presented ongoing suicidal ideation based on psychotic ideas. Thus, neuroleptic treatment was strongly indicated ([Fig. 1]). Further immunohematological work-up revealed the presence of strong anti-neutrophil autoantibodies, consistent with a diagnosis of autoimmune neutropenia ([Fig. 2]). Secondary autoimmune neutropenia due to other reasons could be excluded. Primary autoimmune neutropenia is a well-described disorder in children, but a rare and only vaguely characterized disease in adults. Of importance, recruitment of neutrophils from the bone marrow in the case of an infection is usually not affected in patients with primary autoimmune neutropenia, so that only a small proportion of these patients develop significant infections [1]. Therefore further administration of G-CSF was not indicated.

Fig. 1 Course of leukocyte and granulocyte count over six months. Granulocyte colony- timulating factor G-CSF was administered twice, resulting in a sharp rise of granulocyte count followed by a subsequent decrease. Administration of olanzapine started with a granulocyte count of 476/μL.

Fig. 2 Representative result from the granulocyte immunofluorescence test (GIFT) assay, performed as outlined previously [7]. Briefly, granulocytes were isolated from HLA- and HNA-typed healthy donors and incubated with the patient's plasma. After a washing step, cells were incubated with fluorescein isothiocyanate-labeled rabbit F(ab’)₂-anti-human immunglobulin G, rewashed, and evaluated with a fluorescence microscope. The patient's plasma showed broad reactivity with four distinct granulocyte suspensions irrespective of the HNA and HLA pattern, consistent with the presence of autoantibodies. The presence of neutrophil-specific autoantibodies was confirmed in a glycoprotein-specific enzyme immunoassay (not shown).

We applied olanzapine in slowly increasing doses up to 20 mg per day. Olanzapine is a well established neuroleptic [5] but with a dose-related risk for neutropenia [4]. Neutrophil counts remained on a low level, and no infections occurred during the hospital stay. At follow-up after one year, the patient had not had severe infections or other side effects, his mental state was fairly good and stable, he still lived with his parents and attended vocational training. The leucocyte count (2 300/μL) and neutrophil count (690/μL) were still low. Dosage steps of olanzapine were not related to the neutrophil count.

To the best of our knowledge this is the first reported case of starting maintenance neuroleptic treatment despite agranulocytosis with good outcome. Extended hematological diagnostics which revealed a benign autoimmune disorder was crucial in this case. The course after one year confirmed our approach.

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Correspondence

R. BorbéMD 

Centre for Psychiatry

Die Weissenau

Ulm University

Weingartshoferstraße 2

88214 Ravensburg

Germany

Phone: +49/751/7601 23 78

Fax: +49/751/7601 24 13

Email: raoul.borbe@zfp-weissenau.de