Antipsychotics and neutropoenia: An update

Neutropoenia is a decrease below fi gures deemed normal in the peripheral blood count of neutrophils. For adults the normal neutrophil count varies between 1800 and 8100 neutrophils/ mm [1]. Most cases of neutropoenia in the adult are acquired and due to an increased destruction of granulocytes. Drugs are a common reason for neutropoenia of central origin. The risk of neutropoenia and other blood dyscrasias associated with multiple routinely used drugs is well known. Despite this, the use of these drugs is deemed acceptable if the clinical benefi t for the patient is documented and side effects are controlled [2].


Introduction
Neutropoenia is a decrease below fi gures deemed normal in the peripheral blood count of neutrophils. For adults the normal neutrophil count varies between 1800 and 8100 neutrophils/ mm [1]. Most cases of neutropoenia in the adult are acquired and due to an increased destruction of granulocytes. Drugs are a common reason for neutropoenia of central origin. The risk of neutropoenia and other blood dyscrasias associated with multiple routinely used drugs is well known. Despite this, the use of these drugs is deemed acceptable if the clinical benefi t especially highlight clozapine and olanzapine and to a much lesser extent risperidone, quetiapine or paliperidone [1,3,4].
The aim of this paper is to perform an updated review of the scientifi c evidence available in regard to cases of neutropoenia associated with use of antipsychotics and their clinical management in psychiatry.  for every 7700 patients treated [5][6][7].

Defi nitions, prevalence and risk factors
Data from the Clozapine Pharmacovigilance Programme in the United Kingdom reveal an incidence per 100,000 people/ week of treatment of: 32% incidence in the fi rst 18 weeks, 2.3% incidence between weeks 19 and 52 and 1.8% incidence from week 53 onwards: The cumulative incidence of agranulocytosis for this record is 0.78%. Most cases took place during the fi rst 18 weeks of treatment [8]. Age: more than 50% of cases occur in people aged over 50.
Sex: more cases are identifi ed in women than men. It is believed this is because the psychotropic drug intake of women is higher.
Patients with prior neutropoenia.
Patients with prior blood dyscrasias because of other drugs.

Concomitant use of ACE inhibitors or interferon.
There are populations with genetic susceptibility to neutropoenia such as Yemeni Jewish and Japanese associated with HLA B38 and HLA DRB1, respectively.
The prognosis of cases of neutropoenia associated with psychotropic drugs is worse in people aged over 60, in counts under 100 neutrophils/μL, coexistence of septicaemia and prior morbidities which are mainly renal, cardiac or respiratory [10,11].

Pathogenesis of neutropoenia associated with antipsychotics
It is well known that formation of the nitrenium cation by means of monooxigenase 3 in the leukocyte system is the initial step of haematological toxicity of antipsychotics. It must be recalled that most patients who begin treatment with clozapine undergo a benign leukocytosis which is due to mobilization of leukocytes from the marginal pool and bone marrow. The onset of a decrease in white blood cells would, therefore, be due to reduced production of new neutrophils. This could be mediated by an immune mechanism against neutrophils, mitochondrial oxidative stress that would lead to apoptosis of the neutrophils or direct drug toxicity on the bone marrow [2].

Clinical features of neutropoenia
Most neutropoenia patients are free of symptoms and they are detected after analytical monitoring. Oral ulcers may be a clinical manifestation, as well as non-specifi c symptoms such as general malaise and anorexia. On other occasions, especially when the neutropoenia is severe, the patient visits because of fever and there may even be onset of sepsis. In these cases hospital admission for intravenous antibiotic treatment is necessary. The clinician must watch out for onset of fl u or odynophagia symptoms. Healthcare training for carers and patients on the alarm data is recommended. If neutropoenia is severe (below 500/μL) and prolonged over time, the risk of bacterial infection is added to the risk of fungal infection [9].

Prevention: Pre-treatment evaluation with clozapine
There are a series of contraindicating circumstances during onset of a treatment with clozapine [12][13][14].
Citation: Rodríguez  Before starting a clozapine treatment the following must be performed [12]:  Full history and medical examination that includes weight, height, muscle mass index and blood pressure.

Monitoring of clozapine treatment
Monitoring the neutrophil count in patients under clozapine treatment reduced the incidence of agranulocytosis from Relative Risk (RR) 2 to RR 0.38. Mortality fell to 0.013%. In any case, some authors report that the benefi ts of screening can be overestimated because of the low incidence of agranulocytosis [6,9,15].
weekly blood work up the fi rst 18 weeks.
 monthly blood work up whilst treatment lasts.
 Blood work up 4 weeks from discontinuing clozapine treatment (as neutropoenia is reported over this period).
Currently, it is planned to reduce monitoring as of the fi rst year of treatment because the cost-benefi t ratio is doubtful in patients who did not develop prior neutropoenia [6].
Th e re are alternatives such as capillary blood analysis that can help to improve compliance with monitoring. Moderate physical exercise should be encouraged because this leads to a raised white blood cell count. It should be borne in mind that sometimes it is not the antipsychotic that causes neutropoenia.
It should also be evaluated whether other drugs the patient receives are involved, especially if there is concomitant use of methamizole or beta-lactams [2].
In the event of neutropoenia in which it is suspected that there is a causal drug, performing aspirate/bone marrow biopsy is not indicated. This is performed if the count does not recover in a reasonable time frame once the drug is suspended, with or without treatment with granulocyte colony stimulation factors (G-CSF). Or in the case of other peripheral abnormalities that lead to suspecting a non-pharmacological central cause [9].

Cl o zapine and coronavirus disease 2019
Some recommendations with regard to the coronavirus pandemic have recently been published [12].
The coronavirus 2019 (COVID-19) public health emergency has necessitated social isolation and staying at home.
Based upon existing evidence with respect to clozapine and neutropenia, the FDA guidance and an expert consensus statement [18] suggest the following approach to using clozapine and monitoring minimum Absolute Neutrophil Count (ANC).
 For patients treated with clozapine, one may reasonably decide that obtaining mandated clozapine blood work (ANC monitoring) during the COVID-19 pandemic is impossible or entails unacceptably high risks for patients or others. As an example, patients may be in isolation or in quarantine, or at high risk for mortality if they are infected with COVID-19 while travelling to a clinic or laboratory for blood work.
 One factor that determines whether it is acceptable to waive ANC testing is duration of clozapine treatment.
As an example, it is reasonable to temporarily forego testing in patients who have received the drug for at least one year and have never had an ANC <2000/ μL (or <1500/μL if there is a history of benign ethnic neutropenia).

Clinical management of neutropoenia
For monitoring we should bear in mind the absolute neutrophil count. If this is reduced we must confi rm with a second test. Performing a peripheral blood smear that reveals normal morphology of blood cells and no accompanying cytopoenia will help us rule out other pathologies that may cause neutropoenia. It is estimated that clozapine-associated neutropoenia lasts on average 12-21 days after discontinuing the drug. Table 1 summarises the most common treatment strategy recommended in each case in regard to this drug [12,[19][20][21][22][23][24] .
Som e ins ti tutions are more restrictive and recommend discontinuing clozapine if the neutrophil count is lower than 1500/μL [14].
To trea t neutropoenia with established drugs G-CSF (Filgastrim) can be used. However, these agents, which are outside the scope of neutropoenia caused by oncological agents, are not backed up by solid evidence. They are normally used when neutropoenia is severe. Lithium also raises leukocytes when myeloperoxidase is inhibited. It has been used to prevent neutropoenia in patients taking clozapine [2,3,9].
Th e incid en ce of agranulocytosis with olanzapine is much less than with clozapine. Possibly because management doses are lower. Haematological toxicity of olanzapine is dosedependent. Olanzapine has a similar structure to clozapine. Therefore, it has been recommended as an alternative in patients with neutropoenia induced by clozapine. However, this safety is uncertain because olanzapine metabolites are toxic against neutrophils in vitro [25,26].
In regar d to the remaining second and third generation antipsychotics, the possibility of haematological abnormalities is rare. Leukocytosis and neutropoenia with risperidone has been reported in 4% of patients. Moreover, it has been reported in 2% of patients with quetiapine or paliperidone. No frequency of haematological monitoring has been recommended with these drugs [5].

•
In gener a l using clozapine in children or adolescents is not recommended because there are no safety and effi cacy data. Despite this, it is observed from the short series published that neutropoenia was not more prevalent than in adults. The use of lithium has been reported as successful in children with neutropoenia because of clozapine associated with aripiprazole [2].

Conclusi o ns
• The incidence of neutropoenia with antipsychotics is low. However, it is a potentially severe adverse effect.
• Blood work up in series should be performed when we use clozapine. This is pending a future consensus to adjust monitoring according to each patient's own risk.
• The risk of neutropoenia with second or third generation atypical antipsychotics is much lower than with clozapine. However, there is no consensus on its monitoring.
• It is important to teach patients and families about alarming clinical signs and symptoms that warn the health professional about a potential case of neutropoenia.
In light of these results we can draw the conclusion that careful management of anti-psychotic drugs is necessary. We are familiar with monitoring strategies and signs of alarm we must watch out for to avoid iatrogenic cases which in the worst case scenarios can even lead to death. Against this backdrop, recommendations in Europe are more conservative with raised requirements and controls and USA guidelines are the most fl exible standards.
Once the risk-benefi t of the use of antipsychotic drugs has been evaluated in each patient individually, we can state that these drugs are no more unsafe than other routinely used drugs, such as beta-lactams or methamizole. Therefore, it is possible that drugs with major antipsychotic potential such as clozapine are under used because of the diffi culties in monitoring by the health professional in regard to clinical management and lack of patient compliance. In the future, it would be interesting to perform further pharmacotherapeutic safety studies to identify the most effi cient strategy to monitor clozapine.