Clozapine (Azaleptin, Leponex. Clozasten, Azaleprol)

Pharmacological properties of the drug Clozapine

Tricyclic dibenzodiazepine derivative. Neuroleptic, has antipsychotic and sedative effects. Blocks dopamine receptors in the central nervous system, has peripheral and central anticholinergic, as well as adrenolytic, antihistamine and antiserotonin effects. A distinctive feature of clozapine is that it practically does not cause significant extrapyramidal disorders and does not have a pronounced inhibitory effect. Treatment with clozapine does not cause an increase in prolactin levels in the blood and, therefore, does not lead to the development of gynecomastia, amenorrhea, galactorrhea and impotence.

Use of the drug Clozapine

Adults are usually prescribed on the 1st day at a dose of 25–50 mg. If well tolerated, the dose is slowly increased over 1–2 weeks by 25–50 to 300 mg/day (individual fluctuations in the daily dose from 200 to 450 mg are possible). Frequency of administration - several times a day; Moreover, a larger dose of the drug can be prescribed before bedtime. The maximum recommended dose is 600 mg/day, but some patients may require a dose of up to 900 mg/day; This dose can be achieved only with a very gradual (no more than 100 mg in one stage) increase. After achieving the maximum therapeutic effect, it is recommended to transfer the patient to maintenance treatment with clozapine at lower doses. The maintenance dose should be selected individually, with a gradual (in several stages) reduction of the initial dose. The maintenance daily dose averages 150–300 mg, although for some patients it may be lower. At a dose not exceeding 200 mg/day, clozapine can be taken once in the evening. In case of planned discontinuation of treatment, a gradual dose reduction over 1–2 weeks is recommended. If prompt withdrawal is necessary, the patient's mental status must be monitored. When resuming interrupted treatment, recommendations for an initial gradual dose increase should be followed. In patients with a history of seizures, as well as in persons with cardiovascular diseases and kidney and/or liver diseases, the initial dose of the drug should be low, and the dose should be increased very slowly.

Side effects of the drug Clozapine

The risk of occurrence and/or intensification of side effects increases when clozapine is prescribed in a daily dose exceeding 450 mg. Hematological: granulocytopenia, agranulocytosis (usually develops during the first 18 weeks of treatment); the development of eosinophilia and/or leukocytosis of unknown etiology is possible (especially during the first weeks of treatment). From the side of the central nervous system: most often - drowsiness, increased fatigue; Possible dizziness, headache, relatively rarely - extrapyramidal symptoms, usually of mild severity. There are reports of the development of rigidity, tremor, akathisia, as well as very rare reports of the development of neuroleptic malignant syndrome. From the autonomic nervous system: a feeling of dry mouth, disturbances of accommodation, sweating and thermoregulation, hyperthermia, excessive salivation. From the cardiovascular system: possible tachycardia, orthostatic hypotension, less often - fainting (especially in the first weeks of treatment), relatively rarely - hypertension (arterial hypertension). In rare cases, collapse has been reported, accompanied by depression or respiratory arrest. There are isolated reports of changes in the ECG, the development of arrhythmia, and myocarditis. From the digestive tract and liver: nausea, vomiting, constipation are possible. An increase in the activity of liver enzymes has been reported, and in rare cases, the development of cholestasis. From the urinary system: there are reports of cases of urinary incontinence and urinary retention. Other: weight gain; There are isolated reports of the development of skin reactions. Cases of sudden death have been described, occurring with equal frequency both among people with mental disorders receiving antipsychotic drugs and among patients who do not receive these drugs.

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.

Special instructions for the use of Clozapine

Given the high risk of developing agranulocytosis during treatment with clozapine, it should be prescribed only to those patients with schizophrenia who have no effect from treatment with classical antipsychotics or in case of their intolerance. A prerequisite is also that the patient initially has a normal quantitative and qualitative composition (leukocyte formula) of leukocytes in the blood. During treatment with clozapine, systematic monitoring of the number of leukocytes and leukocyte formula is necessary: ​​weekly for the first 18 weeks and at least once a month thereafter throughout the course of treatment. Caution should be exercised when prescribing clozapine to patients with prostatic hypertrophy and angle-closure glaucoma; diseases of the liver, kidneys, heart. In these patients, systematic monitoring of the function of the liver, kidneys, and cardiovascular system is necessary. Due to the ability of clozapine to cause sedation and lower the seizure threshold, patients should avoid driving vehicles or operating potentially dangerous machinery, especially during the first weeks of treatment. The safety of clozapine during pregnancy has not been established. If clozapine is prescribed during breastfeeding, breastfeeding should be interrupted.

Clozapine

In 1959, the first drug of a new generation of psychotropic drugs was synthesized - clozapine (closarin, leponex, azaleptin), which subsequently opened the way for the synthesis of atypical antipsychotics.

Clozapine appeared on the pharmaceutical market in 1968. In 1975, eight patients in Finland died due to infectious complications resulting from clozapine-induced agranulocytosis. At the end of the 70s, this medication was banned for use in most countries of the world due to the risk of severe side effects when taking it. However, in 1988, D. Kein et al. again suggested the high effectiveness of clozapine in the treatment of schizophrenia. After receiving positive results from a multicenter study of clozapine in the United States in 1990, it returned to the pharmaceutical market.

Chemical group: dibenzodiazepine.

Release form: 12.5, 25 and 100 mg

Pharmacokinetics: half-life from 5 to 15 hours, peak concentration 1-4 hours after administration, stabilization of concentration 3-4 days of therapy, bioavailability - 60%.

Dosing rules: Clozapine therapy is usually started with a daily dose of 12.5 or 25 mg and then gradually over 10 days the dose of the drug is increased by an average of 25 mg per day, monitoring the safety of its use. After reaching a dose of 100 mg, you should stop increasing the dose for several days, waiting for the effect. The average dose of the drug corresponds to 300-600 mg, the maximum - 900 mg. When prescribing clozapine to children, the initial dose of the drug is 12.5 mg per day, increasing the dose in the future by no more than 3-6 mg per kg of weight. The dosage range for elderly patients is 10-100 mg per day.

Most pharmacological guidelines recommend monitoring clozapine plasma levels during treatment. A level of 400 ng/ml is considered preferable for therapy.

Indications: clozapine can be used to treat schizophrenia, especially for the treatment of its resistant variants, since in this case in 30-50% of cases it is possible to achieve a clear clinical improvement (Bochner F. et al, 2000; Bridler R., Umbricht D., 2003 ). Moreover, the clear positive effect of clozapine can continue even after a year of therapy with this drug.

Clozapine is almost seven times more effective than chlorpromazine (aminazine) in the treatment of resistant variants of schizophrenia. The new atypical antipsychotics that were subsequently synthesized were safer than clozapine, but, as a rule, they were inferior to it in the effectiveness of treating schizophrenia.

Indications for treatment of schizophrenia with clozapine

• Resistant variants
• Persistent suicidal thoughts
• Frequent manifestations of aggression and dysphoria
• Comorbid substance dependence
• Severe manifestations of cognitive deficit
• Tardive dyskinesia

Clozapine has a certain thymoleptic effect and, as a result, is able to reduce the symptoms of depression comorbid with schizophrenia. It has been effective in preventing suicide in patients with schizophrenia, especially in patients who have expressed thoughts of suicide for a long time (Purucker M., et.al., 2007).

Constant irritability and manifestations of aggression, signs of tardive dyskinesia are also considered today as an indication for treatment with clozapine. When prescribed clozapine, patients are less likely to discontinue treatment than when taking traditional drugs.

The drug has proven effective in treating not only schizophrenia, but also schizoaffective disorders.

Most patients respond to clozapine therapy within the first month of taking it, but some patients respond to therapy even after 3-4 months of treatment. If clozapine therapy is ineffective within 4-6 months, a change in drug is necessary.

Mechanism of action: clozapine modulates the activity of a number of mediator systems, while significantly blocking D1 and relatively weakly D2, D3, D4 dopamine receptors (D1/ D4 > D2/ D3).

As noted above, clozapine is considered a fairly strong antagonist of dopamine D4 receptors and in this regard is superior to traditional antipsychotics.

The drug also blocks the depolarization of A10-dopamine neurons. This is consistent with data obtained by assessing clozapine-induced increases in c-fos protein expression (a novel marker of cellular activity) in the nucleus accumbens, ventral striatum, anterior cingulate and medial prefrontal cortex. Haloperidol, unlike clozapine, activates the expression of the c-fos protein in structures innervated by dopaminergic neurons belonging to the A9 group, located in the dorsal striatum.

It has an affinity for many receptors, including serotonin (blockade of 5HT2A, 5HT2C is more pronounced than 5HT3, 5HT6, 5HT7 receptors), histamine (H1), acetylcholine, alpha1 and alpha2 adrenergic receptors and cholinergic receptors (muscarinic M1 and nicotinic). When using clozapine, 80-90% of serotonin 5HT2A receptors are blocked by a dose of the drug that simultaneously blocks only 20% of dopamine D2 receptors.

In the experiment, clozapine does not cause catalepsy, does not block stereotypies provoked by apomorphine or amphetamine, and does not increase the level of prolactin in the blood serum.

Side effects: Compared with traditional antipsychotics, clozapine extremely rarely causes early and late extrapyramidal disorders. The absence of symptoms of parkinsonism, akathisia, acute dystonic reactions, and tardive dyskinesia is explained by the low affinity of clozapine for D2 receptors (the blockade of dopamine receptors is more pronounced in the limbic system than in the striatal system). Moreover, the drug can even be used to treat tardive dyskinesia and severe akathisia.

Among the most dangerous side effects of the drug, neutropenia should be noted, which develops during the first 4-18 weeks of therapy (cases of agranulocytosis have been described a year after starting clozapine).

Side effects of clozapine

• Disturbance of the hematopoietic process (neutropenia, agranulocytosis)
• Neurological disorders (epileptiform seizures - 1-2%, myoclonic tics, atonic paroxysms)
• Drowsiness, especially in older patients
• Gastroenterological disorders (constipation, increased salivation, especially at night)
• Cardiovascular disorders (orthostatic hypotension at the initial stage and hypertension at the later stages of therapy, tachycardia, myocarditis, pulmonary embolism) Accommodation disturbance (cycloplegia)
• Metabolic disorders (impaired carbohydrate and fat metabolism, the latter due to antagonism to H1 and 5HT2C receptors)
• Nocturnal enuresis

During clozapine treatment, neutropenia occurs in 1-3% of patients, usually occurring within the first 18 weeks of therapy, and is more likely to occur in older patients and may develop slowly or occur suddenly.

With age, the risk of neutropenia when taking clozapine, according to some authors, decreases, annually decreasing by an average of 17% per decade; on the contrary, the risk of agranulocytosis increases. On average, the development of agranulocytosis is observed in 0.38-1% of patients, and it appears more likely in females than in males.

It is believed that agranulocytosis occurs due to the direct toxic effect of the drug on the hematopoietic (clozapine metabolite norclozapine has a toxic effect on bone marrow cells) and immune systems of the body. Due to the above, it is dangerous to prescribe drugs to patients with schizophrenia, like clozapine, that affect the process of hematopoiesis, for example, carbamazepine.

Prescribing clozapine is especially dangerous for those patients who had neutropenia before starting treatment.

It has been noted that among Africans and residents of the Afro-Caribbean region, the likelihood of developing neutropenia during treatment with clozapine is higher than among other people.

Risk factors for the development of agranulocytosis differ from risk factors for the development of neuropenia, and therefore it has been suggested that neutropenia does not always develop into agranulocytosis.

Agranulocytosis is more likely to be due to a predisposition to this condition and is more common in people of Asian origin receiving clozapine therapy.

During treatment with clozapine and for several weeks after its discontinuation, weekly monitoring of the number of leukocytes in the patient’s blood is mandatory. If leukocytes decrease below 3000 or by 50% of the initial level, immediate discontinuation of the drug is necessary.

If agranulocytosis occurs, the patient must be placed in an isolation room to eliminate the possible risk of infection. To enhance the regeneration of leukocytes, patients are prescribed filgastrim, a granulocyte colony-stimulating factor (Ann S., Coyle J., 2007).

When discontinuing the drug, symptoms of withdrawal syndrome may be observed for a short time: nausea, vomiting, diarrhea, increased salivation; in rare cases, psychosis may occur (cholinergic effect).

Seizures have been reported at doses of clozapine greater than 600 mg per day (carbamazepine should be avoided if seizures occur). The risk of seizures is relatively high, ranging from 3 to 10%, and especially increases with high dosages of the drug. In addition, the drug can cause myoclonic (myoclonic twitching usually precedes a full-blown seizure) and atonic paroxysms. To avoid the development of such complications, it is recommended to start therapy with small doses and then slowly increase the dose of the medication. Some guidelines also recommend clozapine therapy in combination with valproate.

Side effects of clozapine include excessive drowsiness. It is especially noticeable in older people, in the initial stages of therapy and in the process of increasing the dose of the drug. Somewhat less common are increased salivation, weight gain and constipation.

The drug negatively affects the cardiovascular system, promoting orthostatic hypotension (in the later period - hypertension) and tachycardia. A toxic effect of clozapine on the heart muscle has been noted. In the first weeks of treatment, myocarditis may occur.

The drug has a slight effect on the level of prolactin in the blood. Clozapine may disrupt glucose homeostasis through indirect insulin and growth hormone secretion, an effect associated with blockade of serotonin and histamine receptors (Melkersson U. et al., 1999). Disorders of fat and carbohydrate metabolism are currently associated with the effect of the drug on the receptors of the serotonergic system.

It is necessary to take into account the anticholinergic effect of clozapine; with its long-term use, cycloplegia, a disturbance of accommodation, may appear.

Currently, due to the large number of serious side effects, clozapine is rarely prescribed.

Interactions with medications: Co-administration of clozapine with other medications requires special attention (Table 29).

Table 29. Interaction effects of clozapine with other drugs

In the literature one can find recommendations about the benefits of the combined use of clozapine and lithium, since the latter increases the number of leukocytes, however, according to most researchers, the results of such studies are unrepresentative.

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Drug interactions Clozapine

Clozapine can potentiate the central effects of ethanol, MAO inhibitors and CNS depressants (narcotic analgesics, antihistamines, benzodiazepine derivatives). With the simultaneous administration of clozapine and benzodiazepines, as well as in the case of recent treatment with benzodiazepines, the risk of developing hypotensive reactions, collapse, as well as respiratory depression and arrest is increased. Mutual enhancement of effects is possible with the simultaneous administration of clozapine and drugs that have anticholinergic, hypotensive properties, as well as drugs that depress respiration. With the simultaneous administration of clozapine and drugs that have a high degree of binding to plasma proteins (for example, warfarin), it is possible to increase the content of the free fraction of any of the active substances in the blood, which can lead to side effects.

The Russian Federation continues to experience a high incidence of criminal poisoning with clozapine. The proportion of clozapine poisoning in specialized departments of Moscow hospitals is constantly increasing and amounts to 6.3–12.6% with a mortality rate of 12–18% [1, 2], and in some regions of the Russian Federation the annual increase in clozapine poisoning exceeds 100–140% [3] . In the structure of criminal poisonings, clozapine came out on top; cases of poisoning with it account for 99.7% of all poisonings of interest to the investigation [4].

The media have repeatedly reported on criminal poisonings with clozapine with the aim of bringing their “victims” into a helpless state for subsequent robbery [3, 4]. A feature of clozapine poisoning is often the presence of a second toxicant—ethyl alcohol [4]. When clozapine is poisoned, a person “falls asleep” and is unable to resist, so the drug is used as a means to commit illegal actions.

Diagnosis of fatal clozapine poisonings is based on the results of forensic chemical testing. At the same time, the question of interpreting a positive result of determining it in the blood, urine and internal organs is difficult.

For forensic medical examination, the systematization of pathological manifestations of clozapine poisoning is important. In this regard, the task arises of a qualitative and quantitative search for new expert criteria for the diagnosis of acute poisoning based on a comprehensive statistical and model-based analysis of clinical and forensic data. This approach to studying the material is promising in forensic medicine and will increase the reliability and validity of forensic medical research, and the information obtained about the features of the clinical course of acute clozapine poisoning at the present stage is necessary for further improvement of the diagnosis of poisoning in general. Only such an integrated approach, taking into account clinical and morphological manifestations, can resolve the issue of how to qualify cases of detection of clozapine in the environments and tissues of the dead: as acute (fatal) poisoning or as a background condition caused by taking a drug, including for therapeutic purposes.

The purpose of the study is to systematize and summarize existing publications and determine the features of forensic medical diagnosis of fatal clozapine poisoning.

Clozapine is an international nonproprietary name; it is the active substance of such drugs as Leponex and Azaleptin, known in the forensic literature. Clozapine (C18 H19 ClN4) is a dibenzodiazepine derivative that has antipsychotic activity and has a rapidly onset sedative effect, which has led to its abuse to obtain a narcotic effect and use for criminal purposes. The drug is intended for the treatment of schizophrenia, manic states, psychoses, emotional and behavioral disorders, especially often in alcoholism. Available in the form of tablets of 25 and 100 mg, solution for injection (50 mg). Belongs to the group of atypical antipsychotic drugs (a distinctive feature of the group is that the substances practically do not cause extrapyramidal disorders). In addition to the antipsychotic effect, the drug has a sedative, antiemetic and hypothermic effect; has antiserotonergic, antihistamine, peripheral and central m-anticholinergic and alpha-adrenergic blocking properties [3]. In cases of clozapine overdose, the mortality rate is about 12%. Death occurs after taking doses exceeding 2000 mg (80 tablets of 25 mg), but cases have been described in which patients recovered after taking more than 10,000 mg of the drug (400 tablets of 25 mg). The therapeutic effect in adults is achieved with a single dose of 50-100-200 mg; daily dose 200-400 mg; the maximum daily dose is up to 600-900 mg (0.6-0.9 g). A conditionally lethal single dose is considered to be 3 g [4-8], but the literature [5] describes non-fatal cases of poisoning when taking higher doses of the drug (up to 16 g). As a result of a 13-year retrospective foreign study [9], it was found that a 50% risk of developing severe poisoning occurs when taking 0.9 g of clozapine in patients over 50 years of age and 14.5 g in patients under 50 years of age. Clozapine has been used in clinical practice since 1972 [7, 10]. Until recently, it was included in List B of drugs included in the State Pharmacopoeia of the Russian Federation, the prescription, dosage and storage of which must be carried out with caution. Currently, List B has been canceled [11, 12].

The drug is well absorbed from the gastrointestinal tract. Bioavailability 27-60%. The maximum concentration in the blood is determined after 2.5 hours. Communication with plasma proteins is 95%. It is distributed unevenly in biological media: it penetrates the blood-brain barrier, but accumulates in the brain in much smaller quantities than in the liver, lungs, and kidneys. It is characterized by enterohepatic circulation [6, 13].

Metabolized in the liver by the CYP1A2 enzyme system (catalyzed by cytochrome P-450) [14]. The first stage of biotransformation is a series of oxidative processes, the second is conjugation, resulting in the formation of active (desmethylclozapine, clozapine-N-oxide) and inactive (glucuronides, hydroxy- and methylthio derivatives) metabolites [13]. The results of some studies [15-17] indicate the need for a more in-depth study of the toxic activity of metabolites and their role in the pathogenesis of various effects, since the active metabolites of clozapine (clozapine-N-oxide) can undergo reverse transformation into clozapine, thereby maintaining its long-term circulation in the body [13].

Clozapine is excreted from the body in 2 phases: the first is fast, the second is slow: the half-life of the second phase is on average 12 hours (from 6 to 24 hours). About 50% of the administered dose is excreted in the urine and 30-35% in the bile, mainly in the form of metabolites [18].

In our country, clozapine attracted the attention of forensic chemists in the 80s of the last century. In recent years, methods have been developed and improved for the forensic chemical detection and quantitative determination of clozapine and its metabolites isolated from biological objects based on thin-layer, gas-liquid and high-performance liquid chromatography, and IR spectrophotometry. The necessary volume and completeness of a forensic chemical study to draw up a conclusion on the detection of clozapine have been determined [3, 11, 19, 20]. One of the latest domestic works [21], devoted to the development of a method for determining clozapine in blood, urine and liver using high-performance liquid chromatography, indicates that the modern detection limit for clozapine is 0.001 mg%; insulation losses are 40-60% (relative error 10-11%).

It has been established that clozapine and its metabolites are preserved in cadaveric material for approximately 1.5 months, and when the biomaterial is stored in a refrigerator (4 °C) - for at least 3 months [3, 22]. Our practical experience indicates that it is possible to detect clozapine in the organs of an exhumed corpse 22 months after burial.

In foreign literature [23], special attention is paid to the detection of not only clozapine, but also its metabolites: N-desmethylclozapine (norclozapine) and clozapine-N-oxide, as well as the quantitative ratio of native clozapine and norclozapine, which can provide additional information when establishing the time and dose of the substance taken.

Clozapine is often taken in combination with other drugs or while intoxicated. In this regard, it is important to note some features of the interaction of clozapine with other drugs. It is known that its simultaneous use with substances that increase the activity of enzymes of the cytochrome P-450 system (finlepsin, phenitrin, nicotine), especially with ethyl alcohol, leads to faster metabolism and, accordingly, a decrease in the concentration of clozapine in the blood. Co-administration with drugs that reduce the activity of this cytochrome (cimetidine, macrolide antibiotics, a number of serotonin reuptake inhibitors, especially fluvoxamine and caffeine) slows down the metabolism of clozapine [5]. Clozapine blood levels may also increase when taken concomitantly with drugs that have a higher degree of protein binding (for example, warfarin) [5]. All this complicates the assessment and dictates the need to take a more cautious approach to the interpretation of the results of forensic chemical studies when not only clozapine or its metabolites, but also ethyl alcohol are detected in the blood of the deceased.

The clinical picture of poisoning is characterized by a syndrome of central nervous system depression of varying severity depending on the concentration of the substance in the blood. At threshold concentrations, lethargy, drowsiness, and adynamia are noted, while at critical and fatal levels, a coma of varying depths, impaired respiratory function and hemodynamic instability with the development of low cardiac output syndrome are observed. The latter is caused by a decrease in venous return of blood and impaired contractility under conditions of hypoxemia, while cardiac performance is maintained due to high tachycardia [5]. A comatose state may be preceded by a neuroleptic syndrome, which is characterized by confusion, visual hallucinations, psychomotor agitation, and hypersalivation [5].

When analyzing laboratory parameters, attention is drawn to leukocytosis, lymphocytopenia in combination with a decrease in cellular immunity, and an increase in the leukocyte index of intoxication. The results of biochemical blood tests reveal a reduced protein content and an increase in the amount of creatinine, which indicates an increase in endotoxicosis [23]. An important place in the pathogenesis of poisoning is occupied by lipid peroxidation and inhibition of the antioxidant defense system. An indicator indicating an increase in lipid peroxidation is the content of malondialdehyde in the blood and its progressive increase [5, 24]. Hemorheological indicators include an increase in the viscosity characteristics of blood and plasma, fibrinogen content, as well as the aggregation activity of erythrocytes and platelets [5, 23].

The development of a terminal condition and death into the toxicogenic stage of acute clozapine poisoning (1-2 days) is associated with the progression of early complications: disruption of homeostasis, the functions of the central and peripheral nervous systems, and the development of endotoxicosis [5, 25]. Two main variants of thanatogenesis can be distinguished: paralysis of the respiratory center and acute cardiovascular failure [5, 7]. In the somatogenic phase of poisoning (3-6 days), death occurs due to the development of late complications, primarily pneumonia, encephalopathy and pulmonary embolism [2, 5]. The main late complication of acute clozapine poisoning is bronchopneumonia [5]. The background for its development is artificial ventilation, aspiration, as well as venous congestion in the lungs [5, 26]. Noteworthy are lesions of the tracheobronchial tree of varying severity; catarrhal tracheobronchitis is more common, and less commonly, an erosive form of the lesion [5]. Bacterioscopic examination reveals polymorphic microflora [2]. Thromboembolism in clozapine poisoning is considered as a manifestation of its side effect [15, 26], since it can cause increased adhesion and aggregation of platelets, and also creates conditions for a static type of blood flow in severe poisoning accompanied by a coma [27].

Many studies [2, 4] about clozapine poisoning provide information that can help in planning and conducting a forensic medical study of victims in conditions of non-obviousness, when criminal poisoning is suspected. Criminal poisoning with clozapine occurs, as a rule, among men of working age. The corpses of the dead are “suddenly” discovered by passers-by on the street, in forest parks, entrances, on subway platforms, in electric train cars, at train stations, and public transport stops.

Pathological changes in internal organs are predominantly nonspecific in nature and are manifested by discirculatory disorders and dystrophic changes in parenchymal organs, as in case of poisoning with other drugs of neurotropic action. Edema of the brain and lungs, hemorrhages in the gastric mucosa, focal intraalveolar hemorrhages, distelectasis, dystrophic changes in the kidneys and myocardium are noted [2, 7, 28]. With long-term use of clozapine for the treatment of mental illness, changes in the liver and pancreas are detected [2, 5, 24, 28], similar to changes in alcoholism, but considered as a result of the side effects of the drug. In general, morphological signs in acute clozapine poisoning are nonspecific and should be considered in conjunction with the results of forensic chemical research.

Of interest for expert practice and assessment of clozapine poisoning are clinical observations of cases of prolongation of the QT interval on the ECG when taking the drug. If the interval exceeds 500 ms, the risk of serious arrhythmias increases sharply: for example, torsades de pointes, which leads to death in approximately 1 in 10 cases [5, 29]. The risk of sudden death associated with clozapine is thought to be increased in persons with pre-existing heart disease, those taking multiple drugs that affect the QT interval, and those taking high-dose antipsychotic drugs over a period of time. long period [29].

Researchers [30, 31] note an association between clozapine use and the development of potentially fatal myocarditis (so-called clozapine-associated eosinophilic myocarditis) in somatically healthy victims.

Foreign sources [9, 32—34] contain indications of a postmortem increase in the content of clozapine in the blood compared to that before death. The authors associate this with post-mortem redistribution, one of the reasons for which may be the diffusion of the substance from organs with high concentrations (for example, from the stomach) into the blood. It has been experimentally established that the post-mortem increase in the concentration of clozapine in the blood from any “central” vein can increase up to 300%, norclozapine - up to 460%; in the blood from the peripheral vein of clozapine up to 155%, norclozapine up to 185%. The ratio of the concentration of clozapine in the blood from the heart and large “central” vessels of the corpse to the concentration in the blood from the peripheral veins is 2.8 [35]. We believe that when interpreting the results of post-mortem forensic chemical studies, it is necessary to take into account the possibility of a post-mortem increase in the level of clozapine in the blood compared to intravital.

At present, there is no doubt that a true idea of ​​the severity of a chemical injury is provided primarily by the quantitative content of the toxicant in the blood of victims [36]. It should be emphasized that clozapine is characterized by close therapeutic and toxic concentrations, and the individual response of the body to the intake of the substance, as well as previous use of the drug for therapeutic purposes, are of great importance [3, 5]. According to the literature, the lethal concentration of clozapine in the blood is 1.3 mg%, in the liver - 2 mg%, in the kidneys - 2.5 mg% [8]; a toxic effect is observed at a concentration of clozapine in the blood of 0.09-0.7 mg%, in the urine - 0.43 mg%; in the liver, lethal concentrations of clozapine are 0.65-8.5 mg%, in urine - 1.1 mg% [37]. One of the latest foreign studies [38] indicates that the therapeutic concentration of clozapine in blood plasma is 0.35-0.6 mg/l, toxic - 0.6-1.0 mg/l; at a concentration of more than 1 mg/l, a coma may develop. The indicated concentration ranges overlap, and in most sources they contradict each other [39–41]. This is explained by the fact that none of the studies meets modern requirements of evidence-based medicine, since there is no clear and scientifically based evidence that in all cases we are talking about fatal poisoning. In addition, in most of these studies, as in almost all forensic chemistry laboratories in the country, the concentration in the examinations is indicated in milligram percent (mg%), which is a non-systemic unit that is not part of the International System of Units (SI). This circumstance makes it difficult for practicing forensic medical experts to interpret the results obtained and does not allow them to compare the obtained data with global samples of reference toxicological information. Milligram percent is the number of milligrams (mg) of the substance of interest contained in 100 ml of the test solution or 100 g of the substance.

In Russia, GOST 8.417-2002 is in force, which prescribes the mandatory use of SI units both in everyday life and in science and technology. The system unit (SI unit) for measuring concentration is mg/l (1 mg% = 10 μg/ml = 10 mg/l = 0.01 mg/ml).

We came across only one modern domestic study [5], in which, from the standpoint of evidence-based medicine, a toxicometric study of the clinical manifestations and outcomes of clozapine poisoning was carried out. It shows, using specific clinical examples, that the threshold concentration of clozapine in the blood is 0.12±0.06 mg/l, critical - 1.01±0.2 mg/l, lethal - 3.5±1.5 mg/l l. According to modern requirements, it is this interpretation of toxicological data regarding clozapine poisoning, in our opinion, that is the most correct and reasoned.

Conclusion

The possibility of using clozapine for criminal purposes should be kept in mind in all cases of suspicious circumstances and when examining corpses with signs characteristic of acute poisoning. Currently, there are highly sensitive methods for detecting clozapine in biomaterials, making it possible to determine trace amounts of the substance and its metabolites. A forensic medical expert in his practical work must remember that the detection of a toxicant in tissues is not always identical to death from poisoning and can only indicate the use of the substance shortly before death. Morphological changes in acute fatal poisoning with clozapine are predominantly nonspecific and are represented by dyscirculatory disorders and degenerative changes in parenchymal organs.

When deciding the cause of death in cases of examination of corpses in whose biological fluids and organs clozapine was found, one should critically evaluate the result of the forensic chemical study, comparing it with the morphological picture, detected background and concomitant diseases, and also take into account the possibility of clozapine neoplasm and determine the nature of its interaction with other identified substances. A true idea of ​​the severity of a chemical injury is given only by the quantitative content of the toxicant in the blood of the dead. It has been established that the lethal concentration of clozapine in the blood is 3.5 ± 1.5 mg/l. The detection of clozapine in other organs and tissues can be considered as a fact confirming the use of the substance shortly before death, and its role in thanatogenesis is ambiguous and requires significant clarification and special explanation.

In case of criminal poisoning with clozapine, it should be borne in mind that a mixture of clozapine with ethyl alcohol (in any ratio of these two substances) is included in the list of intoxicating substances approved by the Standing Committee on Narcotics Control in 2005 [42]. In cases where, in order to steal someone else's property, an intoxicating substance dangerous to life or health is introduced into the victim's body against his will or by deception to render him helpless, the act is qualified as robbery [43]. In this regard, the fact of detection of clozapine in the biological media of a corpse is important information for law enforcement agencies.

In our opinion, a critical assessment of the results of a positive forensic chemical study as evidence of fatal clozapine poisoning is necessary, especially due to the lack of clear morphological equivalents of this pathology. A comprehensive study of this problem should also be carried out.

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