Haematological toxicity of drugs used in psychiatry

Almost all classes of psychotropic agents have been reported to cause blood dyscrasias. Mechanisms include direct toxic effects upon the bone marrow, the formation of antibodies against haematopoietic precursors or involve peripheral destruction of cells. Agranulocytosis is probably the most important drug-related blood dyscrasia. The mortality from drug-induced agranulocytosis is 5-10% in Western countries. The manifestations of agranulocytosis are secondary to infection. Aggressive treatment with intravenous broad-spectrum antimicrobials and bone marrow stimulants may be required. Of drugs encountered in psychiatry, antipsychotics including clozapine (risk of agranulocytosis approximately 0.8%, predominantly in the first year of treatment) and phenothiazines (chlorpromazine agranulocytosis risk approximately 0.13%), and antiepileptics (notably carbamazepine, neutropenia risk approximately 0.5%) are the most common causes of drug-related neutropenia/agranulocytosis. Drugs known to cause neutropenia should not be used concomitantly with other drugs known to cause this problem. High temperature and other indicators of possible infection should be looked for routinely during treatment. Clozapine is well known as a drug that can cause blood dyscrasias, but olanzapine and other atypicals may also cause similar problems. In addition to genetic factors, there are likely to be dose-related and immunological components to these phenomena. Important lessons have been learnt from the haematological monitoring that is necessary with clozapine and the monitoring has been very successful in preventing deaths related to clozapine-induced agranulocytosis. Continuing research into the mechanisms of drug-induced neutropenia and agranulocytosis may serve to further enhance the safe use not only of clozapine, but also of other agents.     

Recognition and management of drug-induced blood cytopenias: the example of drug-induced acute neutropenia and agranulocytosis

Background: More than several hundred drugs, toxins, and herbs have been reported to cause blood abnormalities, and drugs account for 20 – 40% of all instances of cytopenias. Objective: In the present paper, we report and discuss the recognition and the management of drug-induced acute neutropenia or agranulocytosis (neutrophil count of < 0.5 × 10⁹/l). Methods: A bibliographic search was performed on the PubMed database of the US National Library of Medicine for articles published from January 1990 to January 2008. Additional not published data of our cohort of drug-induced agranulocytosis in the University Hospital of Strasbourg, France were incorporated in this review. Results/conclusions: Idiosyncratic drug-induced acute neutropenia or agranulocytosis is a serious adverse event due to the frequency of severe infections (such as deep infections, septicemia and septic shock) but modern management with broad spectrum antibiotics and hematopoietic growth factors is likely to improve the prognosis. Given the increased life expectancy, increasing use of medications as a therapeutic modality and subsequent longer exposure to drugs, as well as the development of new agents, healthcare professionals should be aware of this adverse event and its management.     

Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors

To determine the role of growth factors in nonchemotherapy drug-induced agranulocytosis, we reviewed 118 published reports of administration of colony-stimulating factors for the disorder. Main outcomes were total duration of neutropenia and mortality. The mean time to neutrophil recovery was 4.6 +/- 3.2 days and 7.7 +/- 5.1 days in patients with a granulocyte count at diagnosis of 0.1-0.5 x 10(3)/mm3 and less than 0.1 x 103/mm3, respectively. The mortality rate was 4.2%. Without therapy with growth factors, the mean time to neutrophil recovery after discontinuation of the offending agent was reported to be 10 +/- 8 days. The mortality rate was 16% in one study. We conclude that hematopoietic growth factors may shorten the duration of neutropenia and reduce mortality in patients with severe drug-induced agranulocytosis.     

Detection and incidence of drug-induced agranulocytosis in hospital: a prospective analysis from laboratory signals

AIMS: Our objectives were to assess the detection and incidence of drug-induced agranulocytosis in two university hospitals using hematology laboratory data. METHODS: A prospective study was undertaken at Toulouse University Hospital (France) and Navarra University Hospital (Spain) for 1 year (from 1 May 2004 to 30 April 2005). Using a computerized process and hematology laboratory data, all neutrophil counts with a value less than 500/mm(3) were registered, allowing identification of inpatients suffering from agranulocytosis during the period of the study. Medical records of all selected patients were then consulted. Cytostatic drugs were excluded from this study. RESULTS: During the period of the study, 225,659 neutrophil counts were performed in both hospitals, of which 2,835 (1.26%) had a neutrophil count less than 500/mm(3), corresponding to 739 patients. Seventeen patients were excluded because of lack of data, and 20 cases of infants younger than 3 months were excluded. Among the remaining patients (n = 702), 23 cases of drug-induced agranulocytosis (excluding cytostatic drugs) were suspected. All cases were classified as "serious" since they led to death in 2 cases, hospitalization or prolongation of hospitalization in 19 cases and threatening of vital prognosis in 2 cases. Withdrawal of suspected drugs was done in all cases with regression of neutropenia in 21 cases. According to hospitalization data, the annual incidence of drug-induced agranulocytosis was 1.62 (1.0-2.6) per 10,000 inpatients in Toulouse University hospital (based on 534 cases) and 3.24 (0.9-8.3) per 10,000 inpatients in Navarra University Hospital (based on 168 cases). The involved drugs were mainly antibacterial (30.4%), immunosuppressive (17.4%), antithyroid (13.0%), antiplatelet (8.7%) and nonsteroidal anti-inflammatory (8.7%) ones. Only seven cases from Toulouse University Hospital were spontaneously reported by physicians during the same period. Thus, the underreporting coefficient (U) was 2.71 (63.2%) in France. CONCLUSION: Our survey allowed us to identify the suspected drug-induced agranulocytosis through a prospective study in a large sample of inpatients using only laboratory data analysis. We also note an important underreporting rate of this serious adverse drug reaction (ADR) to the official French pharmacovigilance system. Laboratory data analysis could be used for identifying serious ADRs.     

Treatment of sulphasalazine-induced agranulocytosis with granulocyte macrophage-colony stimulating factor

Sulphasalazine-induced agranulocytosis is a rare but potentially life threatening complication. A variable mortality rate has been reported, from 6% to 20%, and is related to the duration of neutropenia. Previous case reports have shown that the use of granulocyte macrophage-colony stimulating factor (GM-CSF) in treating drug-induced agranulocytosis may shorten the period of neutropenia and hence lead to improved survival. It may also be a less costly treatment option that supportive care alone due to reduction of hospital stay as a consequence of a shortened duration of neutropenia. We report a case in which sulphasalazine had been used in the treatment of ulcerative colitis and the subsequent agranulocytosis was treated successfully with GM-CSF, something which has hitherto been unreported.     

Pediatric drug safety signal detection of non-chemotherapy drug-induced neutropenia and agranulocytosis using electronic healthcare records

Objectives: This study aimed to develop a procedure to explore the adverse drug reaction signals of drug-induced neutropenia (DIN) or drug-induced agranulocytosis (DIA) in children using an electronic health records (EHRs) database.

Methods: A two-stage design was presented. First, the suspected drugs to induce DIN or DIA were selected. Second, the associations were evaluated by a retrospective cohort study.

Results: Ten and five drugs were potentially identified to be associated with DIN and DIA, respectively. Finally, five (oseltamivir, chlorpheniramine, vancomycin, meropenem, and ganciclovir) and two (chlorpheniramine, and vancomycin) drugs were found to be associated with DIN and DIA, respectively. Of these, the association between oseltamivir and neutropenia (P = 9.83 × 10^–9; OR, 2.10; 95% CI, 1.62?2.69) was considered as a new signal for both adults and children. Chlorpheniramine-induced neutropenia (P = 3.01 × 10^–8; OR, 1.59; 95% CI, 1.35?1.87) and agranulocytosis (P = 3.16 × 10^–7; OR, 3.76; 95% CI, 2.25?6.26) were considered as new signals in children. Other drugs associated with DIN or DIA were confirmed by previous studies.

Conclusion: A method to detect signals for DIN and DIA has been described. Several pediatric drugs were found to be associated with DIN or DIA.     

Incidence and risk factors for agranulocytosis in Latin American countries—the Latin Study

PURPOSE: LATIN is a multinational case-control study designed to identify risk factors for agranulocytosis and to estimate the incidence rate of the disease in some Latin American countries. METHODS: Each study site in Brazil, Argentina and Mexico conducted an active search of agranulocytosis patients in hematology clinics and looked for possible associations with drug use. RESULTS: The overall incidence rate was 0.38 cases per 1 million inhabitant-years. Agranulocytosis patients more often took medications already associated with agranulocytosis than controls (p = 0.01), mainly methimazole (OR 44.2, 95% CI 6.8 to infinity). The population attributable risk percentage (etiologic fraction) was 56%. The use of nutrient supplements was more frequent among patients than controls (p = 0.03). CONCLUSIONS: Agranulocytosis seems to be very rare in Latin America. The lower than expected number of cases identified during the study period precluded estimation of the risk associated to individual drugs, with the exception of methimazol. However, this is the longest series of agranulocytosis cases ever gathered in Latin America, and information on drug exposures was collected prospectively. The conclusion is that drug-induced agranulocytosis does not seem to be a major public health problem in the study regions.     

Non-chemotherapy drug-induced neutropenia - an update

Introduction: To date, non-chemotherapy drug-induced severe neutropenia (neutrophil count of ≤0.5 x 10⁹/L) also called idiosyncratic drug-induced agranulocytosis is little discussed in the literature. In the present paper, we report and discuss the clinical data and management of this rare disorder.

Areas covered: To do this, we carried out a review of the literature using PubMed database of the US National Library of Medicine. We also used data from the American Society of Hematology educational books, textbooks of Hematology and Internal medicine, and information gleaned from international meetings.

Expert opinion: Idiosyncratic agranulocytosis remains a potentially serious adverse event due to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia, and septic shock in approximately two-thirds of all hospitalized patients. In this context, several prognostic factors have been identified that may be helpful when identifying ‘susceptible’ patients. Old age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 10⁹/L have been consensually accepted as poor prognostic factors. In our experience, modern management with pre-established procedures, intravenous broad-spectrum antibiotics and hematopoietic growth factors (particularly G-CSF) is likely to improve the prognosis. Thus with appropriate management, the mortality rate is currently between 5 to 10%.     

Agranulocytoses médicamenteuses idiosyncrasiques : analyse de 7 ans dans un hôpital universitaire français

IntroductionIdiosyncratic drug-induced agranulocytosis is a rare but potentially serious haematological disorder. The pathophysiological mechanisms are complex and poorly understood. We aimed at investigating agranulocytosis drug related causes from the myelograms with “myeloid maturation arrest” performed in our university hospital over the last seven years.MethodsA retrospective analysis of myelograms collected for agranulocytosis was performed from 1st January 2010 to 31th December 2016. We used the method of Bégaud et al. for drug causality assessment.ResultsAmong the 104 myelograms analysed, 41 agranulocytosis were drug-induced, whose 28 were idiosyncratic. Among these 28 cases, 26 different drugs were involved. Agranulocytosis was a known adverse reaction in the summary of the product characteristics for 24 drugs, mainly associated with undetermined frequency (n = 7). Mean onset latency was 38.1 days after starting the drug (calculated for n = 23 cases) and granulocyte growth factors were used in 50% of cases without shortening the mean delay of blood count recovery. Bone marrow presented hypereosinophilia in 29% of cases. Pharmacovigilance reporting rate was 48%.ConclusionA “maturation arrest” in the myelogram is not pathognomonic for idiosyncratic drug-induced agranulocytosis. This rare event require multidisciplinary care involving haematologists, biologists and pharmacovigilance experts. Agranulocytosis reporting rate was high compared with usual adverse drug reaction reporting rate (5 to 10%), probably related to the potential severity of this event.     

Antipsychotic drugs in bipolar disorder

Antipsychotic drugs are useful in the treatment of acute mania and as maintenance treatment. While both typical and atypical antipsychotic drugs are able to diminish manic symptoms, agitation and aggression in acute mania, the atypical antipsychotic drugs enjoy a number of advantages, including significantly less extrapyramidal symptoms, diminished risk of tardive dyskinesia, lack of increase in serum prolactin levels (with the exception of risperidone), improvement in cognition, and possible decrease in suicidality. Most of the atypical antipsychotic drugs have been found to be effective as an add-on treatment (with mood stabilizers and antidepressant drugs) and sometimes as monotherapy in treatment-resistant bipolar patients. Long-acting typical neuroleptic drugs may be useful in the treatment of non-compliant bipolar patients. A small number of patients with schizophrenia treated with risperidone, olanzapine, or quetiapine experience a first episode of hypomania or mania. It is not apparent if this is a true drug-induced event or coincidental. Side-effects of note with the atypical antipsychotic drugs are weight gain (most prominently with olanzapine and clozapine), sedation, and agranulocytosis (clozapine). Atypical antipsychotic drugs are recommended for use in bipolar disorder for acute treatment, maintenance treatment, and for treatment-resistant patients.     

Drug-induced agranulocytosis: impact of different fcgamma receptor polymorphisms?

Drug-induced agranulocytosis is a rare but life-threatening side effect which is possibly based on immunogenetic mechanisms. Some studies regarding agranulocytosis induced by the atypical antipsychotic clozapine dealing with HLA subtyping and enzyme polymorphisms have been performed to elucidate its genetic background. To further screen possibly genetically based pathways of developing agranulocytosis, we assessed clinically relevant polymorphisms of immunoglobulin G or Fcgamma receptors in patients with clozapine-induced (n = 48), ticlopidine-induced (n = 11), thyroid inhibitors-induced agranulocytosis (n = 8), and controls (n = 75). We found significant age-related effects in each of the drug-induced agranulocytoses but no further associations that underline an effect of polymorphisms in FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb genes on drug-induced agranulocytosis. Thus, Fcgamma receptors may not serve as a genetic marker to identify patients at risk for this life-threatening side effect.     

甲巯咪唑致粒细胞缺乏合并ANCA阳性1例并文献复习

抗甲状腺药物是Graves’病的一线治疗药物,粒细胞缺乏是其少见但严重的副作用,发生机制仍不十分清楚,目前认为主要和免疫反应有关。PTU能诱导ANCA的产生及ANCA相关性血管炎的发生,部分患者合并出现粒细胞减少。虽然粒细胞减少症并未列入ANCA相关的疾病谱,近年越来越多文献报道支持ANCA参与粒细胞减少的发生。这里报道一个MMI治疗后出现ANCA阳性合并严重粒细胞减少不伴血管炎的病例,并对相关的文献进行复习。     

Immune-mediated agranulocytosis caused by the cocaine adulterant levamisole: a case for reactive metabolite(s) involvement

The United States Public Health Service Administration is alerting medical professionals that a substantial percentage of cocaine imported into the United States is adulterated with levamisole, a veterinary pharmaceutical that can cause blood cell disorders such as severe neutropenia and agranulocytosis. Levamisole was previously approved in combination with fluorouracil for the treatment of colon cancer; however, the drug was withdrawn from the U.S. market in 2000 because of the frequent occurrence of agranulocytosis. The detection of autoantibodies such as antithrombin (lupus anticoagulant) and an increased risk of agranulocytosis in patients carrying the human leukocyte antigen B27 genotype suggest that toxicity is immune-mediated. In this perspective, we provide an historical account of the levamisole/cocaine story as it first surfaced in 2008, including a succinct review of levamisole pharmacology, pharmacokinetics, and preclinical/clinical evidence for levamisole-induced agranulocytosis. Based on the available information on levamisole metabolism in humans, we propose that reactive metabolite formation is the rate-limiting step in the etiology of agranulocytosis associated with levamisole, in a manner similar to other drugs (e.g., propylthiouracil, methimazole, captopril, etc.) associated with blood dyscrasias. Finally, considering the toxicity associated with levamisole, we propose that the 2,3,5,6-tetrahydroimidazo[2,1-b]thiazole scaffold found in levamisole be categorized as a new structural alert, which is to be avoided in drug design.     

Mechanism of hypersensitivity reactions: proposed involvement of reactive metabolites generated by activated leukocytes

Hypersensitivity drug reactions are a major source of serious adverse drug reactions, yet very little is known about their mechanism. Several drugs are oxidized by activated neutrophils and mononuclear cells to reactive metabolites. Jack Uetrecht explains that the pattern of hypersensitivity reactions associated with these drugs - drug-induced lupus, agranulocytosis, and generalized hypersensitivity reactions - fits a mechanism in which leukocyte-generated reactive metabolites initiate the hypersensitivity reaction. Because activation of the leukocyte is necessary for reactive metabolite formation, one risk factor for a drug hypersensitivity reaction may be an infection or other inflammatory condition.     

Drug-Induced Lichen Planus

Lichen planus is a relatively common skin disorder of unknown etiology. A wide variety of drugs have been implicated in its cause. Using five or more cases of drug-induced lichen planus reported in at least three separate reports with at least one case of probable cause by the scale of Naranjo et al as criteria, sufficient evidence exists that β-blockers, methyldopa, penicillamine, quinidine, and quinine play a role in this disorder. Evidence is insufficient for angiotensin-converting enzyme inhibitors, sulfonylurea agents, carbamazepine, gold, lithium, and a host of miscellaneous drugs. Given available epidemiologic evidence, nonsteroidal antiinflammatory agents probably should also be considered causative. Differentiating drug-induced lichen planus from the idiopathic disorder is difficult; most evidence is based on the dechallenge and rechallenge with the drug when these data are available.     

Human leukocyte antigen typing, response to neuroleptics, and clozapine-induced agranulocytosis in jewish Israeli schizophrenic patients.

The atypical antipsychotic agent clozapine is known to be effective in schizophrenic patients refractory to other medications; however, it induces agranulocytosis in approximately 1-2%. In Jews, this complication is associated with the haplotype HLA B38,DR4,DQ3. The aim of the present study was to determine which human leukocyte antigen (HLA) antigens are involved in clozapine-induced agranulocytosis. We performed HLA typing in 88 Jewish Israeli schizophrenic patients and in 127 ethnically matched healthy individuals. Thirty-eight patients responsive to standard antipsychotic medications were treated with haloperidol, and 50 refractory patients received clozapine. A trend was noted for elevated rates of HLA B38 among control individuals and clozapine-treated patients of Ashkenazi origin compared to individuals of non-Ashkenazi origin, but the findings failed to reach statistical significance. No association was found between HLA class I antigens and the response to haloperidol or clozapine. Neutropenia developed in two clozapine-treated patients and agranulocytosis in one. Two of these three patients were of Ashkenazi origin, and both demonstrated the HLA B38 phenotype. Although the findings did not reach a statistical significance because of the small number of patients, they may support an association between clozapine-induced neutropenia/agranulocytosis and Ashkenazi origin and the HLA B38 phenotype. The rate of agranulocytosis in our sample (2%) is similar to the usual cumulative risk of agranulocytosis but in contrast to its high frequency among Jewish American patients. One possible explanation for this difference is the high rate of Ashkenazi patients in the American sample and the preponderance of non-Ashkenazi patients in our population.     

Dapsone-mediated agranulocytosis: risks, possible mechanisms and prevention

Agranulocytosis is a rare, severe and unpredictable idiosyncratic reaction associated with drug therapy that can lead to life-threatening illness. Typically, the patient presents with a fever and evidence of infection 1-3 months after initiation of drug administration with a neutrophil count below 0.5x10(9) l. Of the drugs linked with this disease, aminopyrine, dipyrone, clozapine, anti-thyroid agents, sulphonamides and dapsone are the best documented. Generally, agranulocytosis is associated with older individuals (>60 years) and those of non-Caucasian descent. The incidence of agranulocytosis in subjects taking oral dapsone in combination with maloprim for malaria is 1 -- 10-20,000 while leprosy patients treated with dapsone exhibit virtually zero risk of agranulocytosis. However, dapsone is unusual in that during the rare but severe inflammatory disease, dermatitis herpetiformis (DH), the risk of agranulocytosis is multiplied between 25 and 33 fold compared with normal patients. It is conceivable that dapsone might exhibit a similar risk in coeliac disease, a condition related to DH. As dapsone plasma levels in DH subjects can be high (2-10 microg/ml) the increased risk of agranulocytosis could be related to drug dosage, or increased immune responsiveness. The high risks in DH patients probably necessitate monitoring of neutrophil cell population in the first 3 months of therapy, while topical usage of the drug in acne treatment in otherwise healthy patients predominantly below the age of 25 is at the opposite end of the risk scale, probably as low as 1 in 10-20,000 patients.     

Determination of levamisole in urine by gas chromatography-mass spectrometry

The United States Public Health Service Substance Abuse and Mental Health Services Administration is alerting medical professionals that a substantial percentage of cocaine imported into the United States is adulterated with levamisole, a veterinary pharmaceutical that can cause blood cell disorders such as severe neutropenia and agranulocytosis. Levamisole HCl is the active ingredient in a number of veterinary drugs approved to treat worm infestations in animals. Levamisole HCl was also the active ingredient in a human drug for oral administration approved on June 18, 1990, as adjuvant treatment in combination with fluorouracil after surgical resection in patients with Duke's stage C colon cancer. This drug was withdrawn from the U.S. market around 2000, and it has not been marketed in the U.S. since then. The objective of this study was to develop a method to determine the amount of levamisole in urine samples. The procedure will be provided to state health laboratories as needed to be used in the evaluation of patients that have developed neutropenia or agranulocytosis in the setting of recent cocaine use. A gas chromatography-mass spectrometry method was validated and tested at two different laboratories, and the method limit of detection for levamisole is 1 ng/mL in urine when using a 5-mL sample. Confirmation of the stereoisomer of levamisole was done by high-performance liquid chromatography using a chiral column.     

Experience of maintaining clozapine medication in patients with 'red-alert zone' neutropenia: long-term follow-up results

According to the recommended guidelines by Novartis, neutropenia in the range of a white blood cell count less than 3000 per mm, or an absolute neutrophil count (ANC) less than 1500 per mm, is classified as being in the 'red-alert zone' during clozapine treatment. If a patient's blood test result falls into this zone, immediate discontinuation of clozapine is recommended, and reinstitution is prohibited. However, in some patients, it is not entirely feasible to implement this standard guideline because of the lack of effective alternatives to clozapine treatment. Through retrospective chart reviews, five patients who had been maintained on clozapine treatment despite red-alert zone neutropenia were selected. The haematological and clinical courses of these patients were followed for more than 600 days and were compared with those of two control patients who discontinued clozapine due to neutropenia. In all five patients, no additional episodes of neutropenia occurred during the observation period despite continued clozapine treatment. However, three of them maintained a lower neutrophil count for the remaining observation period. Four patients responded favourably to clozapine treatment as judged by Clinical Global Impression score. Given the limitations of a retrospective chart review and the small number of patients, we cannot draw any definite conclusions. However, while the guidelines for the prevention of agranulocytosis should be generally followed, it may be that judicious continuation of clozapine treatment is less risk-prone than previously considered in selected cases where only a few feasible alternatives to clozapine are available. Moreover, there is an apparent necessity to develop new measures or methods that can differentiate between benign neutropenia and that leading to fatal agranulocytosis.