Abstract
Clozapine-induced neutropenia is common knowledge and has received significant publicity resulting in well-formulated guidelines for follow up of patients on this medication [1]. Neutropenia induced by other atypical antipsychotics, especially quetiapine, is less widely known and therefore has not resulted in recommendations or awareness amongst clinicians. This may lead to delayed decision making and serious medical complications. These authors were able to find only three other case reports of quetiapine induced leucopoenia in existing literature [2-4]. We describe the case of a man with chronic psychosis who had leucopenia in response to quetiapine monotherapy and propose a few guidelines to minimize the risk of clinicians missing this potentially fatal side effect as the use of quetiapine becomes increasingly widespread in Australia [5].
RS is a 38-year-old male with a long history of paranoid schizophrenia who has received trials of treatment with several atypical antipsychotic agents with unpleasant side effects. He reported olanzapine induced weight gain, risperidone related extra-pyramidal side effects and clozapine associated neutropenia. He was eventually prescribed quetiapine in 2005 with satisfactory control of psychosis in the apparent absence of side effects. The dose was gradually titrated up to 400 mg in 2006 for better control of his psychotic symptoms when he started reporting an increased susceptibility to upper respiratory tract infections, probably viral in origin. Over the next 4 years he continued to present to his GP with an increasing frequency of coughs and colds that seem to worsen in 2008 and 2009. Many of these infections were accompanied by a decrease in his white cell count. This was initially attributed to febrile or reactive neutropenia secondary to a viral infection. The concurrent prescription of Quetiapine and the temporal co-relation with the increased frequency of viral infections was noted only during the fourth admission. This led to a change in the antipsychotic medication used with a significant reduction in the frequency of respiratory infections and a recovery of the white blood cell count to the normal range (4.83 × 109/L). His total white blood cell (WBC) count was 1.07 × 109/L at its lowest (normal range 4–11 × 109/L) and his absolute neutrophil count for the corresponding period was 0.89 × 10 9/L. While on quetiapine his total WBC count was frequently between 2–3 × 109/L. There was concomitant agranulocytopenia and thrombocytopenia. No associated red cell morphological abnormality was noticed. All six admissions to hospital have involved investigations for other etiological causes of pancytopenia (HIV, Hepatitis, CMV, EBV, CT abdomen) without remarkable findings. He was detected to be positive for Influenza B and Parainfluenza A on 2 separate admissions respectively. He satisfied criteria for a drug-induced neutropenia [6].
The mechanism by which quetiapine causes agranulocytosis remains largely unknown. Several different mechanisms have been proposed for drug-induced agranulocytosis with varying degrees of evidence. Amongst psychotropic agents, this phenomenon has been most robustly investigated in the case of clozapine. Mechanisms that dominate the discussion are immune mediated and direct toxicity [7].
Three different immunological mechanisms have been proposed. These include immune complex mediated, hapten and autoimmune-related mechanisms. Immune complexes formed as a response to the drug may selectively adhere to granulocytes or their immature precursor cells and destroy them. Drugs may themselves act as haptens and induce antibodies leading to subsequent destruction of granulocytes carrying the drug. Autoimmune theories involve the induction of antibodies by drugs. These antibodies may be directed against granulocyte-specific structures [8].
Other mechanisms proposed have included theories regarding the induction of free radicals [9] and the formation of an intermediate nitrenium ion causing agranulocytosis either by direct toxicity or via immune mediation [10]. The exact mechanism of quetiapine related agranulocytosis remains unclear although similar underlying mechanisms are possible given the structural similarity between quetiapine and clozapine [11].
We propose therefore that quetiapine should not be the next logical choice for individuals who have already experienced neutropenia on clozapine because of a possible similarity in the mechanism of inducing neutropenia. A complete blood count and picture may be useful to consider prior to commencing a patient on quetiapine. Information about general health, especially an increased susceptibility to common infections should constitute part of the regular enquiry on follow up. Blood counts should be repeated and compared to baseline in patients reporting a higher than normal rate of infections since being commenced on quetiapine.