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Effect of azaleptin (clozapine) on blood cells

Who is clozapine indicated for?

Clozapine (CLZ), a dibenzodiazepine developed in the 1960s, is considered an atypical antipsychotic approved for the treatment of treatment-resistant schizophrenia (TRS). Clozapine is more effective than any other first-generation (FGA) or second-generation antipsychotic (SGA) drugs in the treatment of treatment-resistant schizophrenia. Almost two-thirds of those patients who do not respond adequately to treatment with FGA or other SGAs may respond adequately to treatment with clozapine.

Dangerous Side Effects

Clozapine was approved in 1989 for the treatment of treatment-resistant schizophrenia after demonstrating better efficacy than chlorpromazine. However, more recent studies have reported adverse effects of clozapine, particularly neutropenia (white blood cell count (WBC <3000/µL) and agranulocytosis (ANC <500/µL) resulting in death. One study in the United Kingdom and Ireland reported reported a prevalence of neutropenia of 2.9% and agranulocytosis of 0.8% among patients taking clozapine.Because of this risk, the US FDA has mandated monitoring of WBC and absolute neutrophil count (ANC) before starting clozapine and periodically thereafter. In October 2015, the Clozapine Risk Assessment and Mitigation Strategies program updated recommended ANC levels and eliminated WBC monitoring.

Red blood cells

The literature describes cases of anemia that occurred during treatment with clozapine.

Leukocytes

Clozapine is associated with a variety of hematologic side effects, including leukopenia, neutropenia, agarnulocytosis, leukocytosis, and eosinophilia. Clozapine may decrease or increase the number of white blood cells and neutrophils. Clozapine appears to act on two levels: directly by increasing the number of free radicals that stimulate proapoptotic genes (p53, bax alpha and bik) and at the same time indirectly by stimulating the release of cytokines (TNFa, IL-2, IL-6 and G -CSF) enhance the expression of anti-apoptotic proteins, thereby inducing myelocyte differentiation and maturation, so the balance between pro-apoptotic and anti-apoptotic factors may be decisive in the final count of leukocytes and neutrophils. It is likely that genetic factors will determine the occurrence of severe leukopenia and agranulocytosis in an unpredictable and non-dose-dependent manner. Several researchers have discovered the possible occurrence of leukocytosis; but in fact its frequency appears to be higher than the incidence of neutropenia and leukopenia in the case of treatment with antipsychotics. According to some authors, an increase in the average number of leukocytes and neutrophils is possible with the start of treatment with clozapine. This increase is very pronounced at first and stabilizes after 3-4 weeks of therapy. Levels then remain higher than baseline until week 18, with a maximum peak at week 13 for leukocytes and at week 10 for neutrophils

Agranulocytosis

The use of CLZ is associated with agranulocytosis, reported in 0.38-0.8% of treated patients, with 12 deaths associated with complications of agranulocytosis. Agranulocytosis and neutropenia are also possible with olanzapine, since this drug is structurally similar to clozapine. Clozapine is well known as a drug that can cause blood dyscrasias, but olanzapine and other atypical antipsychotics can also cause similar problems. In addition to genetic factors, there are likely dose-related and immunologic components of drug effects. Among the drugs used in psychiatry, antipsychotics, including clozapine (risk of agranulocytosis approximately 0.8%, mainly in the first year of treatment) and phenothiazines (risk of agranulocytosis of chlorpromazine approximately 0.13%), and antiepileptics (particularly carbamazepine, risk of neutropenia approximately 0.5%) are the most common causes of associated neutropenia/agranulocytosis. All patients treated with clozapine showed no differences in age and gender compared with those who developed hematological changes. The incidence of hematological side effects of antidepressants was significantly lower (about 0.01%). Data on hematologic outcomes in patients who continue clozapine treatment after neutropenia is established are sparse, as even mild neutropenia leads to mandatory discontinuation of clozapine in most countries. However, neutropenia is common in both patients with schizophrenia treated with clozapine and in patients never treated with clozapine, so most neutropenia during clozapine treatment is probably not caused by this antipsychotic. Although clozapine has a wide variety of side effects, the literature highlights that more than 70% of patients who start clozapine remain on it for a long time. A pharmacogenetic test for agranulocytosis with adequate predictive validity is unlikely and will likely be associated with ethical issues. The risk of agranulocytosis is managed in most developed countries by mandatory blood monitoring in patients receiving clozapine (any patient whose neutrophil count falls below 1500/mm3 is required to stop taking clozapine). In the UK, patients taking clozapine must register with a clozapine monitoring service, where weekly monitoring is required for the first 18 weeks of treatment. For the next 34 weeks, neutrophil monitoring is performed every other week and then monthly after the end of the first year of monitoring. The risk of agranulocytosis is estimated at 0.68%, but after the first year this risk decreases 10-fold. The mortality rate for agranulocytosis is estimated to be 2.7–3.1%, so the absolute mortality rate for patients receiving clozapine for agranulocytosis is very low, at about 0.02%. People of certain ethnic groups, such as Yemenite Jews and 25–50% of black Africans, typically have low neutrophil counts ranging from 1.0 to 1.5 without any observed adverse clinical effects such as more frequent bacterial infections. These people are said to have benign ethnic neutropenia (BEN).

Neutrophils

According to British guidelines, treatment with clozapine is stopped when the neutrophil count falls below 1500/mm3. In the United States, physicians may continue to prescribe clozapine treatment to patients with a neutrophil count less than 1000/mm3 if, in the physician's judgment, the benefits of clozapine therapy outweigh the risk of severe neutropenia. The occurrence of mild (12.8%), moderate (4.3%) and severe neutropenia (0.5%) was frequently identified in patients taking clozapine. Moderate (5%) and severe neutropenia (0.8%) are more common in patients with schizophrenia who have never taken clozapine, although neutrophil counts were performed approximately half as often as when taking clozapine. Patients treated with clozapine were more likely to have only mild neutropenia than those who had never taken clozapine. Most patients who discontinue clozapine treatment after entering the "red zone" (neutrophils <1500/mm3) would probably not develop agranulocytosis if they remained on treatment, especially if their neutropenia is between 1000-1500/mm3 3 range. In Europe, a patient taking clozapine for 40 years was 18.5 times (0.37%/0.02%) more likely to die from a road traffic accident than from agranulocytosis.

Treatment with clozapine appears to predict mild neutropenia, an event that is usually clinically insignificant but may likely increase the likelihood of discontinuation of clozapine treatment. Women have a higher risk of developing neutropenia, with hazard ratios ranging from 1.70 to 2.00, depending on the observed range of neutropenia. Agranulocytosis during clozapine treatment has been reported to be more common in women. Neutropenia is also significantly more common at lower ages, consistent with what has been shown in larger studies. However, of those patients who develop mild neutropenia (neutrophils 1500 - 1900/mm3), none subsequently develop agranulocytosis. One study reported that the rate of neutropenia during clozapine treatment was 11.8%, compared with 17.6% for those taking other second-generation antipsychotics. Note that mild to moderate neutropenia is not a reliable predictor of clozapine-induced agranulocytosis. The exact mechanism of neutropenia caused by clozapine is unknown, although it may be related to the drug's effect on leukocyte precursors. Neutropenia usually appears within 3 months of starting clozapine. Additionally, the risk is higher in certain patient groups (African heritage, Yemenis, West Indians, and Arabs). Patients with lower ANC at clozapine initiation and older age appear to be at higher risk. The use of a granulocyte-colony-stimulating factor such as filgrastim (at an average dosage of 0.6 to 0.9 mg) is often considered a "rescue" treatment for neutropenia and agranulocytosis. The mechanism of action of Filgrastim is associated with the production and proliferation of neutrophils. Several articles in the 1990s reported the effectiveness of short-term treatment with this drug for low levels of WBC or ANC. In one study, neutropenia (absolute neutrophil count <1500/mm) occurred in 23 (13%) patients and agranulocytosis (absolute neutrophil count <500/mm) in one (0.6%) patient. The cumulative probability of developing initial HAE after 1 year of clozapine treatment was 16.1% (95% confidence interval 9.7%-22.5%). Eleven (48%) of the 24 patients who developed HAE were successfully retested on clozapine. Eight (5%) of 172 patients in this sample ultimately discontinued clozapine due to HAE (one agranulocytosis, seven neutropenia). In adults in Western countries, the risk of developing neutropenia and agranulocytosis following clozapine administration is approximately 3% and 0.8%, respectively. If treatment with clozapine was continued for six months, the risk of agranulocytosis caused by clozapine is similar to the incidence of this rare disease with drugs such as chlorpromazine, which are prescribed without supervision. In some countries, active monitoring for neutropenia/agranulocytosis is not carried out at any stage. The decision to discontinue clozapine as a result of hematologic side effects or seizures is distressing for the psychiatrist and often detrimental for the patient. Because the risk of recurrent agranulocytosis is much higher in these patients, various methods to counteract recurrent blood dyscrasias have been considered, including the use of granulocyte colony-stimulating factor and lithium. According to some authors, the appearance of agranulocytosis, as well as the risk of tuberculosis, does not depend on the dose of clozapine, which indicates a connection between these disorders and the function of the immune system. However, another study showed a dose-dependent effect of clozapine on neutropenia.

Eosinophils

There have been reports in the literature of fever and diarrhea associated with the use of clozapine. However, the etiology of these symptoms is not clear. Eosinophilic colitis was suspected in these cases, although there was never any pathological confirmation of this hypothesis of findings. The researchers noted the presence of an increased erythrocyte sedimentation rate in this case, as is often observed in eosinophilic colitis. Histological examination of eosinophilic colitis usually shows the presence of patchy clusters or sheets of eosinophils in the lamina propria and crypt epithelium. The histopathology observed in patients is typically consistent with eosinophilic colitis. Eosinophilic myocarditis is a rare form of myocarditis characterized by myocardial infusion consisting primarily of eosinophils. It is known that it can develop at a rate of 0.2-3% with long-term therapy, especially with clozapine. Standard treatment cannot be established due to the rarity of the disease and difficulties in determining the etiology. When examining areas of the myocardium using a light microscope, general conclusions were drawn: myocyte damage was accompanied by a patchy distribution of perivascular and interstitial inflammatory infiltrate rich in eosinophils. These entities may have developed as a result of a hypersensitivity reaction due to long-term use of antipsychotic drugs. Eosinophilic myocarditis occurs as a rare clinical entity and is probably a subtype of myocarditis that is not always recognized. Failure in clinical diagnosis and delay in treatment can lead to irreversible myocardial damage. Endomicrobial biopsy is still the gold standard in the diagnosis of eosinophilic myocarditis. The literature describes cases of eosinophilia during treatment with quetiapine (4 weeks after the start of treatment with quetiapine at a dose of 50-200 mg/day). The maximum reported absolute eosinophil count in this case was 7.63 x 109/L (normal range <0.5 x 109/L), but the level normalized within 4 weeks of stopping quetiapine and no myocardial damage was observed. Clozapine is the most common antipsychotic drug to induce eosinophilia, but it has also been reported in patients using other atypical antipsychotic drugs such as risperidone and olanzapine. Eosinophilia caused by antipsychotic drugs is thought to be an allergic response of the immune system; blocking neurotransmitter H1 receptors leads to an increase in histamine and therefore an increase in eosinophils in the peripheral blood. Among commonly used antipsychotic drugs, clozapine has the most potent H1 receptor blocking effect; which may explain the relatively higher incidence of eosinophilia among patients receiving clozapine than among patients using other types of antipsychotics. Like clozapine, quetiapine is also a receptor antagonist with a similar, although weaker, blocking effect on histamine H1 receptors, so it is not surprising that it may also cause eosinophilia. Expert observations suggest that eosinophilia caused by antipsychotic drugs usually occurs between 7 and 42 days after starting the drug, with the average start time being 21 days after starting the drug. Clozapine-induced eosinophilia has been reported in several studies in patients receiving this drug. The largest study with 2404 patients in Italy found the incidence there to be 2.2% based on the criteria of greater than 0.4 x 109/L. Cases of pancreatitis, hepatitis, colitis, nephritis and myocarditis associated with eosinophilia have been reported. Interestingly, the incidence of myocarditis is high in Australia but low in the rest of the world.

Lymphocytes

Radioligand assays have shown that clozapine is not incorporated into lymphocytes but appears to exert its effects by binding to specific surface sites. . Conventional in vitro mitogenic stimulation of peripheral blood lymphocytes with phytohemagglutinin (PHA) showed a clear suppression of the response by approximately 50% in all clozapine- and haloperidol-treated patients. The in vitro effects of haloperidol and clozapine on PHA stimulation by lymphocytes in normal subjects were determined by 3H-thymidine uptake and secretion of interleukin-2, interleukin-4 and interferon-gamma. Both clozapine and haloperidol inhibited thymidine incorporation and cytokine secretion at drug concentrations above 1 μM, achieving complete inhibition at 50 μM. Similar inhibitory effects of clozapine and haloperidol have also been observed in the mixed lymphocyte response of mouse lymphocytes (Leykin I., et.al., 1997). Clozapine and haloperidol inhibit the proliferation of human lymphocytes, but, more importantly, the in vitro stimulation of T lymphocytes in patients with drug-induced schizophrenia with anti-CD3 produces lower proliferative responses compared with those observed in well-matched controls. In summary, studies have shown a decrease in lymphoblast viability after exposure to supratherapeutic concentrations of clozapine

Monocytes

The literature reports a case of monocytopenia accompanying clozapine-induced agranulocytosis with successful use of GM-CSF (filgrastim from granulocyte colony-stimulating factor; sargramostim GM-CSF). It is believed that the effect of clozapine on the hematopoietic precursor (the colony-forming unit of granulocytes-macrophages) causes both monocytic and myeloid lineages. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) can be used to reduce the incidence and duration of neutropenia associated with clozapine. The median duration of neutrophil recovery time after discontinuation of clozapine and initiation of cytokine treatment was 7 days (range, 2–13 days) for patients with agranulocytosis (absolute neutrophil count <0.5 x 10 cells/L). Clozapine Metabolites Some studies have shown that stable active metabolites of CLZ, such as N-desmethyl clozapine (DMC), may be associated with neutrophil counts in patients. The mechanism of the decrease in neutrophils in patients treated with clozapine is still not well understood. The metabolism of clozapine is thought to involve an unstable reactive metabolite, the nitrene ion, which is thought to covalently bind to macromolecules such as proteins or cause overproduction of reactive oxygen species. Reactive oxygen species and neutralization of nitrene ions involve the use of reduced glutathione. It should be noted that in patients with refractory schizophrenia, circulating glutathione levels are reduced. . In this regard, the metabolic transformation of CLZ with the formation of reactive oxygen species and nitrene ion is carried out by the NADPH oxidase / myeloperoxidase system and, mainly, CYP3A4, CYP2D6 and CYP1A2, and this transformation may cause a decrease in the number of leukocytes. Another possibility for a similar effect is that CLZ itself may act on leukocytes to promote cell death through apoptosis. The researchers found an 8-fold increase in intracellular CLZ concentrations in patients suffering from leukocytopenia compared to control patients without side effects. Thus, CLZ can directly activate nitrene ion through two isoenzymes, promoting hemotoxicity. Some studies have shown that stable active metabolites of CLZ, such as N-desmethyl clozapine (DMC), may be associated with neutrophil counts in patients. DMC has been reported to be more toxic than clozapine in vitro. There is a significant correlation observed between plasma CLZ levels and patients' neutrophil and leukocyte counts. This relationship is important because the mechanism of clozapine-induced agranulocytosis, although unclear, is believed to be a result of drug metabolism. Study results showed that there is a negative correlation between plasma CLZ levels and blood neutrophil and leukocyte counts, but not with DMC, suggesting that neutrophil and leukocyte toxicity is related to CLZ metabolism. The risk of inducing blood haematotoxicity should not be neglected by initiating treatment with drugs such as β-lactam antibiotics or metronidazole, for example in patients already receiving clozapine. The HLA-DQB1 haplotype has a strong genetic component, which may allow the identification of a subgroup of patients with exceptionally high risk of agranulocytosis (5.1% positive predictive value). This finding is also noted with carbamazepine therapy, particularly in Jewish patients, in whom biomarkers HLA-B38, DR4, and DQw3 provide a positive signal for potential CLZ-induced agranulocytosis. Large numbers of apoptotic neutrophils were found in clozapine-treated patients who developed agranulocytosis. Therefore, drugs that may induce oxidative stress in leukocytes and therefore reduce the antioxidant defenses needed to prevent clozapine-induced pro-oxidative deleterious effects in mitochondria should be discontinued before clozapine is started. It is worth noting that clozapine is more effective than haloperidol, as well as Compared with atypical antipsychotics such as olanzapine and risperidone in terms of preventing inflammation, in particular reducing the level of proinflammatory cytokines. At the same time, individual studies have shown that atypical (clozapine, olanzapine, risperidone) and typical (haloperidol) antipsychotics modulate the production of proinflammatory cytokines (TNF-α, IL-6, IL-4), interferon-γ and/or cytokine receptors (IL-1RA, soluble IL-2, IL-6 receptors)

Platelets

Treatment with clozapine can lead to both thrombocytopenia and thrombocythemia.

Clozapine drug overdose, symptoms and treatment

Drowsiness, coma, areflexia, confusion, agitation, delirium, increased reflexes, convulsions, increased salivation, mydriasis, impaired visual acuity, changes in body temperature, tachycardia, arterial hypotension, collapse, arrhythmia, myocardial conduction disorders, respiratory depression. Treatment: gastric lavage; if necessary, prescribe activated carbon. Symptomatic treatment while monitoring the function of the cardiovascular and respiratory systems; control of water-electrolyte balance and COR. In case of arterial hypotension, the use of adrenaline and its derivatives should be avoided. Medical supervision is required for at least 4 days due to the possibility of late reactions. Peritoneal dialysis and hemodialysis are ineffective.

List of pharmacies where you can buy Clozapine:

Moscow
Saint Petersburg