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Abstract

Schizophrenia is a chronic neuropsychiatric illness defined by the appearance of positive, and negative symptoms and/or cognitive impairment. Antipsychotic drugs are predominantly used in the treatment of psychotic disorders, but not all patients with schizophrenia respond to every antipsychotic medication. Clozapine is one of the best atypical antipsychotics and is highly effective in treating treatment-resistant schizophrenia. Evidence suggests that clozapine appears to be effective in lowering the risk of suicide, extrapyramidal side effects, and relapse in patients with schizophrenia. Per contra, clozapine is not the first-line treatment due to its unalterable aftereffects such as agranulocytosis, metabolic syndrome, seizures, and rarely, eosinophilia. Eosinophilia can be life-threatening. Eosinophils infiltrate different tissues and cause inflammation in multiple organs causing end-organ damage. The current study aimed to report the incidence of eosinophilia associated with clozapine use in patients with schizophrenia. Literature on clozapine-induced eosinophilia is relatively scarce. Understanding the progression and management of clozapine-induced eosinophilia and its end-organ effects is imperative. While there is insufficient data about the guidelines in the management of clozapine-induced eosinophilia, this study contributes to understanding the patterns of the disease progression with clozapine dosage. A case study was done on a patient with schizophrenia and autistic spectrum disorder who was on clozapine. Data on how eosinophil levels varied with clozapine dosing was analyzed and documented. The evidence of clozapine dosage affecting eosinophil and C-reactive protein levels in this patient was summarized in a table and a narrative review.

Keywords

Clozapine case report eosinophilia antipsychotics

Introduction

Schizophrenia is the most common psychotic disease, with a global prevalence of approximately 1%.¹ The disease is characterized by the presence of delusional beliefs, hallucinations, and disturbances in thought, perception, and behavior. Various studies indicate that 20%–30% of patients with schizophrenia meet criteria for treatment-resistant schizophrenia,² which is defined as persistent or moderate delusions or hallucinations after failing two trials of antipsychotic medicines.

Clozapine is an atypical second-generation antipsychotic agent with an established and valuable role in the treatment of these patients. Studies have shown its superiority when compared to other antipsychotics. It has proven to be effective, reducing overall morbidity and suicidality in this population.³ Nevertheless, the use of clozapine is also associated with a number of side effects and careful monitoring of them is a very important aspect of management of the patients receiving the same. Common side effects of clozapine are agranulocytosis, myocarditis, metabolic syndrome, seizures, sialorrhea, and sedation.⁴ While there has been plenty of research on the common side effects of clozapine, few researchers have taken eosinophilia in consideration as a significant side effect of clozapine. Clozapine-induced eosinophilia can be a benign reaction with a transient course and spontaneous remission or it can predict subsequent life-threatening conditions such as neutropenia, myocarditis, eosinophilic colitis, pancreatitis, and toxic hepatitis.^5–8 It is also worth noting that hypereosinophilia can present itself both in its transient benign form, or as eosinophilia related to organ damage.⁸ Therefore, the aim of this study is to highlight the need to treat this condition and draw attention to it in order to prevent deleterious complications of this medication.

In this study we present a review of the literature on cases of clozapine-induced eosinophilia and present a clinical case of a patient with treatment-resistant schizophrenia who developed eosinophilia during the first weeks of treatment with clozapine. The eosinophilia presented by this patient was dependent on the dose of clozapine. The patient was closely monitored for the development of inflammatory reactions and end-organ damage. This case adds to the existing literature that clozapine-induced eosinophilia is mostly a benign and transient reaction that develops during the first weeks of treatment.^9–11 There is limited information on the management of clozapine-induced eosinophilia, but close monitoring with eosinophil count, inflammatory markers, liver function tests (LFT), and echocardiography (ECG) changes should be considered, and discontinuation of clozapine treatment should be considered if end-organ damage is suspected.

Case report

Our patient was a 22-year-old, single, unemployed male of South East Asian descent, living at home with his parents and older brother with an established diagnosis of schizophrenia and autistic spectrum disorder, and was brought to the hospital after he physically assaulted his mother in the context of worsening auditory hallucinations. The patient was born and raised in Chicago. His illness caused dysfunction within his family. At school, he had a history of being bullied. He used saline drops to relieve his rhinitis and was stable at that moment. He had previously used clotrimazole cream to treat fungal dermatitis in the groin area.

When brought to the hospital, the patient was noted to display disorganized behaviors. He maintained minimal eye contact, was responding to internal stimuli and was agitated. His speech was slurred and pressured. He was labile in mood, and his affect was intense and incongruent. His articulation was poor, and he had an illogical thought form. He reported command hallucinations, telling him to harm his mother and other people around him. He, however, denied having any suicidal or homicidal ideations. He had poor insight and impaired judgment.

The patient’s initial symptoms started at the age of 12 years when he experienced auditory hallucinations, which were command in nature. At that time, he was also suffering from paranoid delusions. He thought his friends were talking about him on Facebook. Because of his delusions, he cursed at his friends and wrote derogatory comments on their posts. He was less interested in the things he used to like doing, showed less care in grooming himself, withdrew from social situations, and exhibited less emotion. At the age of 12, he stopped attending school due to the symptoms mentioned above.

Later, he was diagnosed with early onset schizophrenia and autism spectrum disorder with problems understanding language (receptive language deficit) and with problems sharing thoughts and feelings (expressive language deficit). Even though he was compliant, the patient was violent at the time of presentation and did not respond to prescribed antipsychotics. Additionally, he exhibited the Fregoli phenomena. The Fregoli syndrome is a delusional misidentification syndrome when the patient believes that a familiar person has assumed a peculiar physical look while being psychologically the same.¹²

He had previously been treated with various antipsychotics, and after those failed, he was put on clozapine. Olanzapine 20 mg, quetiapine 800 mg, risperidone depot (50 mg intramuscular every 2 weeks), which caused severe akathisia, and zuclopenthixol were among his previously unsuccessful treatments. He was overly sedated on 10 mg of zuclopentixol, and when the dosage was gradually increased to 20 mg, a severe dystonic reaction occurred. It was then tapered and stopped over a period of 2 weeks.

His ECG, LFT, TFT, elevated sedimentation rate (ESR), and creatinine kinase values were all within acceptable ranges after examinations. Urine culture revealed no growth. No ova, cysts, or parasites were found in the stool. He had negative p-anti-neutrophil cytoplasmic antibodies (ANCA) and c-ANCA results. His MRI brain scan revealed a partially empty sella. Changes seen in schizoaffective disorders on MRI, such as minor prominence of the cortical sulci in the posterior parietal region, were also observed in this patient.

The patient received 25, 50, 75 mg, and finally, 125 mg of clozapine. The Figure 1 below shows that as the dose was increased, eosinophil and C-reactive protein levels rose. When the clozapine dosage was increased to 150 mg, the level of eosinophil climbed to 1.2%; when it was increased to 175 mg, the level rose to 1.6%. Once the dose was lowered to 150 mg, the highest level of eosinophils, that is, 1.7%, was noted. Later, the dose was reduced to 125 mg, which yielded a level of 0.5% eosinophils. To treat this dosage-dependent side effect, the dose of clozapine was gradually lowered and then maintained at that lower amount, as shown in the graph below (Figure 2). The patient was consistently observed over a period of 2 months. The patient’s eosinophil count remained consistent at 0.5% with minimal to no systemic side effects noted over a period of 1 month. The patient was regularly followed up along with blood tests every 3 months and remained stable on 125 mg clozapine.

Figure 1.

Timeline of clozapine-induced eosinophilia.

Figure 2.

Timeline of clozapine-induced eosinophilia (Graphical representation).

Discussion

It is well established that the antipsychotic medication clozapine can cause blood dyscrasias, the most concerning of which is agranulocytosis.⁴ Several recent publications (Table 1) have identified that the incidence of eosinophilia may also be of concern, as eosinophilia is now believed to be an important marker of potentially serious inflammatory conditions in patients treated with clozapine. Clozapine-induced eosinophilia often occurs in association with inflammatory processes and end-organ damage, with myocarditis being the most cited example.^4,5,27,28 When there is evidence of organ-specific inflammation, clozapine is normally discontinued to prevent end-organ-damage. In the instances where clozapine-induced eosinophilia occurs without evidence of end-organ damage, it is less clear whether or not clozapine should be discontinued. Unlike clozapine-induced neutropenia, there are no standardized monitoring recommendations for eosinophilia that occurs in the context of clozapine treatment, and there is debate in the literature over how to manage it.

Table 1.

Case reports and systematic reviews of clozapine-induced eosinophilia with some clozapine rechallenge attempts.

Author, year, country	Study	Management and prognosis	Clozapine rechallenge trial?	Rechallenge length	Rechallenge dosage	Rechallenge dosage
Monteleone et al.,¹³ Portugal	Case report	Discontinued clozapine and eosinophil count returned to normal	Not reported	Not reported	Not reported	Not reported
Rehimini et al.,¹⁴ Canada	Case report	Discontinued clozapine. Provided low dose prednisolone	Not reported	Not reported	Not reported	Not reported
Kikuchi et al.,¹⁵ Japan	Case report	Discontinued clozapine on day 30. After that, the eosinophil count gradually decreased to within the normal range by day 40	Pt refused	Not reported	Not reported	Not reported
Filippis et al.,¹⁶ Italy	Systematic review	• Systematic hospitalization was required for all patients• Treatment involved clozapine discontinuation for all patients• Other treatments included immunosuppression and antihistaminic agents• Some were discharged with antipsychotic medications	Rechallenge with clozapine was undertaken in two patients	Not reported	Not reported	Not reported
Lally et al.,¹⁷ Ireland	Case report	• Continued clozapine treatment• Eosinophils normalized by day 8	Yes	23 days	250 mg then 500 mg	Not reported
Demmelo-Rodríguez et al.,¹⁸ Spain	Case report	• 24 h after the withdrawal of clozapine, the patient’s fever disappeared definitively and the patient gradually recovered completely on a physical level	Not reported	Not reported	Not reported	Not reported
Ho and Lin,¹⁹ Taiwan	Case report	Eosinophilia persisted 4 days later	Not reported	Not reported	Not reported	Not reported
McArdle et al.,²⁰ Australia	Case report	• Suspecting schistosomiasis patient was given two doses (1800 mg) of praziquantel, however eosinophilia remained• Clozapine was ceased, 1 month after discontinuing his clozapine, his eosinophil count returned to baseline	Yes	5 months	Not reported	5 months after recommencing clozapine, his eosinophil count is 0.73
Kadiyala et. al.,²¹ India	Case report	Patient was continued on clozapine and divalproex sodium and with these he showed gradual improvement	Not reported	Not reported	Not reported	Not reported
Aneja et al.,⁹ India	Case report	• Case 1: View of the response to clozapine and no symptoms o Dose was gradually increased to 200 mg/day o However, on 26th day of clozapine her eosinophil count increased to 42% o Clozapine was stopped and she was started on haloperidol o The eosinophil count reduced to 18% with absolute eosinophil count of 2880/cmm• Case 2: Patient was continued on clozapine and the dose of clozapine was increased to 150 mg/day o Over the next 5 weeks her eosinophil count varied between 5% and 8%. The eosinophil count settled down to 1%–2% and she tolerated 150 mg/day of clozapine with no other hematological abnormality o She continues to receive clozapine for 6 months without any increase in eosinophil count	Case 1: Yes, Case 2: No	2 weeks	200 mg/day	• During the initial 2 weeks of re-challenge her eosinophil count fluctuated between 12% and 15%• Later on, the eosinophil count settled down to 2%–5% and she was continued on clozapine
Hashimoto et al.,²² Japan	Case reports	• Patient was administered amoxicillin 750 mg/day on days 14–17 and cefepime 500 mg/day on days 17–20. However, on day 20, her white blood cell count increased to 9000 cells/mm³ (eosinophil count unavailable)• Discontinued clozapine therapy on day 20. After discontinuing clozapine, all of the patient’s symptoms and physical findings began to improve	Not reported	Not reported	Not reported	Not reported
Kang and Lee,²³ South Korea	Case report	After 5 days without clozapine, showing the total leukocyte count was 4200/mm³ with 10.5% (441/mm³) eosinophil	Not reported	Not reported	Not reported	Not reported
Nielsen et al.,²⁴ Denmark	Systematic review	Results suggest that prompt discontinuation of clozapine without rechallenge is indicated for agranulocytosis	Not reported	Not reported	Not reported	Not reported
Majumder et al.,²⁵ India	Case report	The eosinophil count also came down to normal limit during the sixth week of initiation of clozapine therapy	Not reported	Not reported	Not reported	Not reported
Roberts et al.,²⁶ USA	Case report	Approximately 2 weeks after initiation of clozapine, Mr. B became febrile. At the time, his clozapine dosage was 100 mg/day. Clozapine was stopped	Yes	2 weeks	Titrated 25 mg every few days	• pt was continued on clozapine with frequent blood testing that included ESR and C-reactive protein level• If pt’s total eosinophil count rose above 1.5 × 10⁹/L then he will be reassessed

Clozapine is an Food and Drug Administration-approved atypical antipsychotic medication for treatment-resistant schizophrenia.²⁹ Treatment-resistant schizophrenia is defined as persistent or moderate delusions or hallucinations after failing two adequate trials of antipsychotic medicines. Clozapine has been widely used after its introduction because it induces relatively few extrapyramidal effects and has shown therapeutic benefits for patients who have failed to respond to other drugs. Other advantages of clozapine include reduced risk of suicide and tardive dyskinesia, improved cognition, and fewer relapses.³ However, clozapine is not indicated as a first-line drug because its use has been associated with a number of side effects such as agranulocytosis, myocarditis, metabolic syndrome, seizures, sialorrhea, etc.⁴ Rarely, clozapine is associated with the side effect of eosinophilia.

Eosinophilia, a non-dose-dependent side effect, has been reported as a rare adverse effect of clozapine. The incidence of eosinophilia in clozapine-treated patients reported in the literature varies enormously from 0.2% up to as much as 62%.³⁰ Clozapine-induced eosinophilia is generally a benign event considered as an allergic reaction, mostly with a transient course and spontaneous remission. However, in some cases, it can predict subsequent life-threatening conditions such as neutropenia, myocarditis, eosinophilic colitis, pancreatitis, and toxic hepatitis.^5–8 Drug-induced eosinophilia has been defined as an eosinophil count greater than 600/mm³ on peripheral blood smear and hypereosinophilia as an eosinophil count greater than 1500/mm³ of blood.³¹

The literature on clozapine-induced eosinophilia is relatively scarce. Most of the literature consists of case reports in which the authors report that eosinophilia, whenever it develops, is usually seen during the initial phase of clozapine treatment, usually within the first 3–6 weeks of therapy.^9–11 In these studies, it is also observed that, in most cases, clozapine-induced eosinophilia resolves spontaneously without the need to modify the drug dose or discontinue it. In none of the cases was clozapine discontinuation required, and in most cases the eosinophilia resolved spontaneously 3–4 weeks after initiation. Marcelino and de Rosalmeida Dantas described a case where clozapine was discontinued at the value of 1500/mm³ eosinophils but restarted after normalization.¹⁰ The patient did not develop eosinophilia again. Patients who have discontinued clozapine as a result of confirmed agranulocytosis tend to experience a rapid and severe recurrence of neutropenia on clozapine rechallenge, which does not appear to be the case for many patients who develop eosinophilia when treated with clozapine. There are small numbers of reports in the literature describing patients who have had a successful rechallenge of clozapine having previously stopped treatment due to eosinophilia without associated organ-specific inflammation. Roberts et al.²⁶ reported that from eight patients who were rechallenged with clozapine, only two of them developed eosinophilia with signs of end-organ damage. In most cases, eosinophilia recurs after rechallenge with clozapine, but to a lesser degree, and is followed by normalization of the eosinophil count despite the continuation of clozapine treatment. Therefore, in cases where clozapine has been discontinued due to eosinophilia without evidence of organ-specific inflammation, clozapine rechallenge with further hematological monitoring should be considered.

In the case report presented in this study, the patient developed eosinophilia shortly after starting clozapine treatment, the eosinophilia observed in this case report was clozapine dose-dependent, and the patient was closely monitored with eosinophil counts and polymerase chain reaction levels. Cardiac monitoring, LFT, and other studies were performed to identify other possible causes of eosinophilia, but all reports obtained were within normal limits. After decreasing the clozapine dose from 175 to 125 mg, the eosinophil levels began to decline despite continued clozapine treatment. Therefore, our case adds to the existing literature that, in the absence of damage to other organs, clozapine can be safely continued. However, close monitoring is recommended. Pons et al.³² (+) recommend adhering to current regulations on monitoring patients on clozapine treatment with weekly complete blood counts for the first 18 weeks of treatment, monthly follow-up for the remainder of the first year, and bi-monthly follow-up thereafter. Moreover, Datta and Solomon⁵ state that patients starting clozapine should be actively monitored for myocarditis during the first 4 weeks, with special care during week 3. They also recommend including cardiac markers in weekly blood work along with inflammatory markers.

The pathophysiology of clozapine-induced eosinophilia is not yet well understood, but proposed mechanisms include a type I hypersensitivity reaction,¹⁹,33 and a direct toxic effect on the bone marrow.^10,33 It is also possible that both mechanisms might co-exist or that other different mechanisms might also be involved. Clozapine-induced eosinophilia may be transient or may present with inflammation and end-organ damage such as myocarditis.⁵ Eosinophilia has been reported in approximately 14% of myocarditis cases occurring in patients treated with clozapine, as well as in some cases of pericarditis/pericardial effusion.^27,28 However, since many patients develop eosinophilia and do not develop subsequent myocarditis or pericardial disorder, it is not known whether eosinophilia is a reliable predictor of carditis. Due to the wide variety of side effects ranging from mild to severe life-threatening events, more studies on this theme are needed with larger samples and extensive monitoring.

The literature on the management of clozapine-induced eosinophilia suggests that the decision to continue clozapine is determined by the presence or absence of end-organ damage. Literature emerging from case reports suggests that if inflammation or end-organ damage is suspected (e.g., pancreatitis, hepatitis, nephritis, and myocarditis), clozapine treatment should be discontinued immediately, and in such cases, even though eosinophil counts and abnormal enzyme levels return to normal, patients should not be rechallenged with clozapine. However, if the eosinophilia occurs without signs or symptoms of organ inflammation, it may be justified and safe to continue clozapine or to re-challenge if clozapine was discontinued, as the most likely outcome will be resolution of eosinophilia 3–4 weeks after initiation. Patients presenting with moderate to severe eosinophilia should preferably be treated in a psychiatric ward of a general hospital, to ensure adequate evaluation and clinical support. The decision to discontinue treatment must be made for each patient individually, and the risks and benefits of discontinuing or continuing clozapine therapy must be carefully considered, always keeping in mind that the clinical benefits must outweigh the risks.

Conclusion

Clozapine-induced eosinophilia is a significant issue that needs to be addressed. How to cure organ damage or side effects brought on by eosinophilia without ceasing clozapine is not well covered in the literature. Clozapine is one of the main antipsychotics recommended for treatment-resistant schizophrenia, therefore stopping the prescription will limit treatment options and may worsen the psychotic symptoms. The development of standardized guidelines by clinicians for observing and managing elevated eosinophil levels brought on by clozapine therapy would be beneficial. We believe that by highlighting the need of treating this condition and bringing attention to it, our study will inspire future clinicians to keep looking into ways to control eosinophilia-induced end-organ damage without discontinuation of clozapine in treatment-resistant schizophrenia patients.

Footnotes

We would like to acknowledge the patient for allowing this case report to be published.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research,authorship,and/or publication of this article.

Funding

The author(s) received no financial support for the research,authorship,and/or publication of this article.

Ethical approval

This case report does not involve any experimental research on animals or human patients,ethical approval is not necessary.

Informed consent

Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.

ORCID iD

Thusanth Jogarajah

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