Clozapine

Clozapine was historically the first representative of the class of so-called “ atypical antipsychotics, ” that is, antipsychotics that differ from the traditional ones by a low likelihood of extrapyramidal side effects, better tolerance and less impact on prolactin secretion.

Clozapine was synthesized in the 1960s . After 8 of 16 patients died in Finland in the 1970s who developed agranulocytosis when taking clozapine, this drug was banned in the United States ^[2] and many other countries ^[3] , but continued to be used in some countries . In 1990, it was re-sold in the USA after it was found out that it is effective for schizophrenic psychoses that are resistant to therapy and is less likely to cause side effects typical of antipsychotics in general ^[2] .

The chemical structure is a tricyclic compound having elements of similarity with tricyclic antidepressants and partially with benzodiazepine tranquilizers . The first metabolite in the biotransformation chain of clozapine in the liver is norklosapine (N-desmethylclozapine), which has all the same pharmacological properties as the parent compound. One of the metabolites of norklosapine in the body is benzodiazepine , which partially determines the strong anti-anxiety activity of clozapine.

Clozapine is, in a sense, “the most atypical,” the most atypical of atypical antipsychotics, since it causes less extrapyramidal disorders in the entire range of clinically applicable doses than other atypical antipsychotics — risperidone (risplept), olanzapine (ziprex) and even quetiapine (seroqueline) at high doses, they are close in properties to traditional antipsychotics and can cause dose-dependent extrapyramidal disorders.

Clozapine has a strong antipsychotic, moderate antimaniacal and moderate tricyclic-like (associated with the effect on the reuptake of monoamines) antidepressant activity in combination with a pronounced hypnotic , sedative and anti-anxiety effect. Blocks various subtypes of dopamine ( D ₁ , D ₂ , D ₃ , D ₄ , D ₅ ), serotonin (5-HT _1A , 5-HT _2A , 5-HT _1C ), muscarinic (M ₁ , M ₂ , M ₃ , M ₅ ), histamine (H ₁ ) and adreno (α ₁ , α ₂ ) receptors; possesses agonism properties for M ₄ receptors ^[4] .

A low proportion of extrapyramidal disorders (0–20%) and the absence of tardive dyskinesias are associated with an agonistic effect on dopamine D2 receptors in the mesocortical region of the brain with a simultaneous suppression of dopaminergic activity in the mesolimbic pathway . Central muscle-relaxing effects are associated with the effect of the drug on GABA receptors .

Independent antidepressant effect (blockade of monoamine reuptake) in clozapine begins to occur at doses of the order of 150-200 mg / day, lower than doses that have a pronounced antipsychotic effect (300-600 mg / day), but higher than the doses at which nonspecific anti-anxiety, sleeping pills and sedative effects begin to appear (25-50 mg or more, depending on the degree of excitement and anxiety).

Due to the very strong anti-anxiety activity, clozapine is particularly selective for acute depersonalization syndrome , quickly, strongly and selectively eliminating the acute depersonalization and derealization in patients with depression. The effectiveness of clozapine in relation to chronic depersonalization is much lower, but also very significant.

The characteristic pharmacological features of clozapine are the inhibition of the activation reaction recorded on the electroencephalogram during electrical stimulation of the reticular formation of the midbrain , a pronounced central and peripheral anticholinergic effect, peripheral adrenolytic effect; the drug does not have a cataleptogenic effect; reportedly inhibits dopamine release by presynaptic nerve endings.

It is clinically characterized by a strong antipsychotic effect in combination with a sedative component in the absence of extrapyramidal side effects characteristic of traditional, typical antipsychotics, which is possibly associated with the central anticholinergic effect of the drug. It does not cause strong general inhibition, like chlorpromazine and other aliphatic phenothiazines .

Clinical improvement with clozapine therapy in people with schizophrenia is achieved much more often than with typical antipsychotics. It is highly effective against productive symptoms, including those resistant to other antipsychotics. Effective at the risk of suicide , persistent hostility and aggressiveness. With regard to cognitive impairment, the results of clinical trials yielded conflicting results: in some indicators, clozapine improved, in others, it did not affect cognitive impairment or even worsened ^[4] . There is evidence that clozapine may cause symptoms of obsessive-compulsive disorder in patients with schizophrenia due to its pronounced antiserotonergic effect ^[5] .

According to any indications, the drug cannot be used as a first-line drug due to the frequent (1-2%) development of a formidable and sometimes deadly complication - granulocytopenia ^[6] , up to agranulocytosis and aplastic anemia .

Clozapine is indicated for patient resistance to other antipsychotics (if at least two traditional antipsychotics taken in the usual dosage over a long period of time do not improve the clinical or subjective state), as well as in case of severe side effects, mainly extrapyramidal, in the treatment other antipsychotics. A guarantee is needed for the implementation of appropriate medical and control measures that necessitate the material and technical base for blood control and special training of medical staff.

In antipsychotic doses (300-600 mg / day), they are used for delusional-delusional, catatonic-hebephrenic, catatonic-hallucinatory conditions and states of psychomotor agitation in schizophrenia , in case of manic syndrome in the framework of bipolar affective disorder . In some cases, the drug is effective for resistance to treatment with other antipsychotics (antipsychotics) ^[7] .

In small doses (12.5-25-50 mg / day), the drug is often used as a sleeping pill, sedative and anti-anxiety medication for insomnia and sleep disorders of various origins, anxiety, neurosis , anxiety and agitated depressions , depressions with depersonalization. It is also used for psychopathy in excited patients, with aggressiveness , dysphoria , affective vibrations and disorders.

In antidepressant doses (150-200 mg / day and higher), it is sometimes used as an independent antidepressant for endogenous depression, primarily with depersonalization syndrome, anxiety, agitation, agitation , severe insomnia, or accompanied by psychosis.

Frequent use of clozapine to achieve sedation and as a sleeping pill is criticized in high-authority sources as not corresponding to its main profile of indications for use in therapy ^{[8] [9]} . It is noted that clozapine in many cases is prescribed without sufficient reason and for other purposes, without taking into account the risk / benefit ratio ^[9] .

Assign inside (after eating) 2-3 times a day. In connection with the risk of dangerous complications, it is recommended to start taking clozapine with a dose of 12.5 mg once or twice a day with a gradual increase to a therapeutic dose ^[10] (these complications include hypotension , fainting, and severe sedation , which with prolonged treatment tolerance is being developed ^[11] ). It is not recommended to increase the dose by more than 25 mg per day. A further increase in dosage is carried out no more than 100 mg per week ^[12] .

A single dose of clozapine for adults is 50-100-200 mg; the average daily dose in the treatment of psychosis is 300-600 mg; the maximum single dose of 450 mg, the maximum daily dose of 900 mg. For maintenance therapy and outpatients, 25-200 mg per day are prescribed (in the form of a single dose taken in the evening or at night before bedtime). If necessary, a solution of clozapine is administered intramuscularly.

• Hypersensitivity to clozapine or to any other component of the drug ^[13]
• Inability to regularly monitor the patient’s blood count ^[13]
• Diseases of the blood ^[14] or hematopoietic system ^[15]
• A history of the hematopoietic system (including reversible) as a result of the use of clozapine or other drugs
• Uncontrollable epilepsy ^[13]
• Alcoholic or other toxic psychoses , drug intoxications , coma ^[13]
• Vascular collapse and / or depression of the central nervous system of any etiology ^[13]
• Spasmophilia ^[15]
• Myasthenia gravis ^[15]
• Severe diseases of the liver, kidneys ^{[14] [15]} , cardiovascular system ^[15] , bile ducts
• Glaucoma ^[14]
• Prostate Hypertrophy ^[15]
• Atony of the intestine ^{[14] [15]}
• Pregnancy ^[15] and lactation.

It is not recommended for use in children and adolescents under 16 years of age.

Clozapine is preferably used as monotherapy. There is an extensive list of drugs in combination with which the use of clozapine should be avoided: other antipsychotics (e.g. phenothiazines and depot antipsychotics), antidepressants , analgesics , antirheumatic and anti-inflammatory drugs , antiepileptic , thyreostatic, antidiabetic, antihypoglycemic, antiarrhythmic, antiarrhythmic, , antifungal, antihistamines , antimalarials.

With great care, clozapine should be used for:

• organic brain diseases
• psycho-organic syndrome
• thrombosis
• chronic coronary heart disease
• drug allergies and other intolerance reactions
• in elderly and debilitated patients
• combinations with sedatives, hypnotics , anticholinergics , antihypertensives, benzodiazepines , adrenaline , lithium , levodopa

In treatment with clozapine, excessive sedation ^[16] , drowsiness, confusion, headaches , dizziness , tremors , muscle stiffness , akathisia , myoclonic twitching, dry mouth ^[13] , orthostatic hypotension , tachycardia , constipation , nausea , vomiting , muscle may occur weakness, increase of body weight, dysfunction of the sweat glands, hypersalivation (excessive salivation, occurs in approximately 31% of patients ^[17] , according to other data, up to 80% ^[18] ), short fainting episodes catalepsy ^[11] , ileus , paraliti eskaya ileus ^[13] , disturbance of accommodation , priapism ^[19] , decreased libido ^[18] , urinary incontinence , urine retention, fatigue, fever, benign hyperthermia , dysregulation of sweating and body temperature ^[13] , rarely - Development vascular collapse leading to cardiac arrest and / or breathing. Arrhythmia , pericarditis , thromboembolism ^[13] , hypertension , fatal myocarditis , cardiomyopathy ^[20] , pneumonia ^[21] are possible. In rare cases, the development of side effects such as delirium ^[16] , malignant antipsychotic syndrome ^{[4] is} possible. Possible development of jaundice , hepatitis ^{[13] [19]} , acute pancreatitis , interstitial nephritis , impaired renal function, renal failure ^[13] .

In the treatment with clozapine (as well as olanzapine ), the most clinically significant increase in body weight is most pronounced compared with therapy with other antipsychotics ^[22] . An increase in body weight is observed in 4–31% of cases. In rare cases - impaired glucose tolerance , diabetes mellitus even in patients without a history of hyperglycemia or diabetes mellitus; in very rare cases, severe hyperglycemia, which can lead to ketoacidosis or hyperosmolar coma, even in patients without a history of hyperglycemia or diabetes mellitus. Perhaps the development of hypercholesterolemia , hypertriglyceridemia ^[13] .

Obesity, which can occur as a result of taking antipsychotics, increases the risk of cardiovascular disease, stroke , cholelithiasis , osteoarthritis , sleep apnea and respiratory diseases , malignant tumors of the endometrium , breast , prostate and large intestine . The mortality rate with the development of obesity increases sharply ^[23] .

According to studies, clozapine increases the risk of impaired glucose tolerance and the development of diabetes mellitus ^[4] , while not only obesity, but also other factors can play a role ^[24] . According to the data of D. Henderson (2000), diabetes develops in 36.6% of patients who took clozapine for 5 years ^[9] .

Cases of epileptic seizures are also observed. Their risk is an average of 2.8%; with an increase in dose, this risk increases: at low doses (<300 mg / day) it is 1%, at medium (300-599 mg / day) - 2.7%, and at high (> 599 mg / day) - 4 ,four %. The risk of seizures also increases with a rapid increase in the dose of the drug. The rate of increase in dosage should not exceed 25-50 mg / day. ^[four]

Extrapyramidal symptoms are lighter and less frequent than those developing with typical antipsychotics. Unlike other antipsychotics, clozapine was not associated with acute dystonia ^[13] , and parkinsonism and akathisia are rare. In addition, it is suggested that clozapine does not cause tardive dyskinesia - although several similar cases have been described, their relationship with clozapine has been unclear. A connection was noted between the widespread prevalence of this drug and a decrease in the incidence of tardive dyskinesia. The risk of malignant antipsychotic syndrome is very low, and therefore clozapine is the drug of choice in patients who have previously experienced this complication ^[25] .

When taking clozapine, leukopenia , neutropenia, eosinophilia , leukocytosis , agranulocytosis , lymphopenia , thrombocytopenia , thrombocytosis , anemia are possible ^[13] . Although agranulocytosis in most cases disappears after discontinuation of the drug, it can lead to sepsis and prove fatal. Most cases of agranulocytosis develop during the first 18 weeks of therapy ^[13] . The probability of developing agranulocytosis in the first six months of administration is about 1% ^[26] , after six months it decreases to 0.1%, after a year to 0.01% ^[27] . It is worth noting that this side effect is not dose-dependent (it does not depend on the dose of the drug ^[11] ). The first signs of agranulocytosis can be symptoms resembling flu , fever , as well as sore throat , inflammation of the gums , oral mucosa, sluggish healing wounds, boils . Multiple oral ulcers and perianal ulcers may develop ^[11] .

In 1993, the results of a monitoring program were published in the first year after clozapine was resumed in the United States. Of the 11 555 patients who received this drug for 12 and 18 months, the detection rate of agranulocytosis was 0.80% and 0.91%, respectively. In most cases, agranulocytosis develops in the first three months of treatment (84%) ^[28] .

Agranulocytosis can develop quickly or gradually. Its risk is higher in patients taking, in addition to clozapine, other drugs that can inhibit hematopoiesis ^[25] . The risk of developing agranulocytosis increases with age, while in women it is higher than in men ^[28] .

In 2007, a genetic test was developed to assess the relative risk of agranulocytosis. Two different single nucleotide polymorphisms of the HLA- DQB1 gene predetermine either an increased risk of complication - 2.5 times higher than average values, or reduced - 2 times lower (coefficient 0.5) ^{[29] [30]} .

With prolonged treatment, clozapine can cause functional hypertrophy of the liver.

Constipation due to taking clozapine can sometimes lead to the development of life-threatening complications: intestinal obstruction , paralytic intestinal obstruction, ischemia , necrosis and perforation of the intestinal wall. In connection with these complications, fatal cases were noted. If constipation occurs, timely treatment is necessary ^[31] .

The use of clozapine can lead to the development of anticholinergic syndrome ^[32] .

Clozapine during pregnancy causes a child to develop agranulocytosis in the first 6 months of life, while agranulocytosis leads to death in one third of cases. Orthostatic hypotension in pregnant women, developing as a result of taking clozapine, can lead to a deterioration in placental blood flow . Clozapine also increases the secretion of oxytocin and may enhance the contractile activity of the myometrium ^[33] .

Clozapine can lead to inhibition of excretion in liver and kidney damage, increase the risk of seizures in patients with epilepsy, worsen the condition with glaucoma, prostate adenoma , dysuria , intoxication (including alcohol) psychoses ^[34] .

Clozapine should be used exclusively under medical supervision. Before starting treatment, it is necessary to conduct a general blood test to determine the leukocyte formula ^[4] (preferably several blood tests for comparison ^[11] ), to assess the general condition of the patient, to examine the cardiovascular system ^[4] , liver and kidney function ^[11] . In the presence of heart disease, the possibility of complications from the cardiovascular system must be taken into account. Treatment begins with a low dose (12.5-25 mg once or twice a day), the dosage is gradually increased, focusing on tolerability, until a therapeutic effect is achieved. Faster dose increases can lead to severe hypotension , drowsiness, and epileptic seizures. During the period of increasing the dose, you need to monitor the state of the cardiovascular system, regularly carry out an orthostatic test (determining the heart rate and blood pressure in the supine and sitting position), and ask if dizziness occurs in this case ^[4] .

The patient should be warned to immediately report all symptoms that may be signs of myocarditis (fever, weakness, chest pain, palpitations, tachycardia , shortness of breath, edema). If such symptoms appear, the patient should be examined and, if suspicion of myocarditis remains, refer to a cardiologist . Indications for cardiac examination include, in addition to suspected myocarditis, also tachycardia, arterial hypotension, decreased pulse pressure, respiratory failure , edema, changes in the ST segment and T wave on the ECG , arrhythmia and eosinophilia , especially if these symptoms appear in the first months of treatment ^{[4 ]} .

The incidence of agranulocytosis and the mortality rate decreased significantly as a result of the introduction of mandatory systematic monitoring of the number of leukocytes and the absolute number of neutrophils , therefore, precautionary measures are mandatory ^[13] . A blood test with the determination of the number of leukocytes and neutrophils in the first six months of treatment should be carried out every week, then every 2 weeks up to a year ^{[12] [13] [35]} , then - after a year - at least once a month throughout the entire period of taking clozapine ^[35] . After the withdrawal of clozapine, blood control should be carried out for several weeks ^[36] . A blood test should also be performed within 6 months after delivery in children whose mothers received clozapine during pregnancy ^[37] .

Clozapine therapy does not start at a leukocyte level <3500 μl ⁻¹ , as well as history of myeloproliferative diseases . With maintenance therapy, it is necessary to warn the patient so that he immediately reports any signs of infection (sore throat, fever , weakness, drowsiness). The level of leukocytes <2000 μl ⁻¹ or neutrophils <1000 μl ⁻¹ are signs of agranulocytosis . In this case, clozapine is immediately canceled, the leukocyte count is determined daily with a leukocyte count, the signs of infection are monitored, and if necessary sternal puncture : in case of inhibition of leukopoiesis inhibition, the patient is placed in a sterile box. When the number of leukocytes is 2000–3000 μl ⁻¹ or neutrophils 1000–1500 μl ^−1, clozapine is also canceled and the leukocyte count is determined daily with a leukocyte count, and signs of infection are monitored ^[4] . An indicator of the need to cancel clozapine is also a decrease in the number of leukocytes by 30% ^[36] (or, in another opinion, by 50% ^[12] ).

With the development of agranulocytosis, they begin active therapy aimed at eliminating complications, such as sepsis , and stimulating granulocytopoiesis . Clozapine should not be reassigned to patients who have undergone agranulocytosis: in this case, relapse is almost inevitable ^[4] .

Clozapine should also be stopped immediately if there are signs of renal failure , prostatic hypertrophy, angle-closure glaucoma, or impaired intestinal motor function ^[19] .

With the development of a convulsive state, treatment with clozapine is canceled and can be resumed after 24 hours at lower doses ^[19] . In the future, the dose should not exceed half of the last dose that did not cause seizures ^[25] .

To prevent the development of metabolic and endocrine disorders while taking clozapine, as well as some other antipsychotics, it is necessary to control body weight ^{[38] [39] [40]} and body mass index ^{[39] [40]} before starting to use it and during taking it. fasting glucose (or hemoglobin A1c ^[41] ), plasma lipid levels ^{[4] [38] [39] [40]} . To detect hyperglycemia, it is also advisable to measure not only fasting glucose, but also 2 hours after glucose intake ^[42] . In patients with risk factors (family history, overweight), glucose monitoring should be carried out every 2-4 months ^[41] .

Against the background of taking antipsychotics such as clozapine, you need to be attentive to the patient's lifestyle and diet. Food should be as low in calories as possible, and lifestyle - as feasible as more active; while diet and exercise require careful dosing ^[43] . It is recommended to reduce the intake of saturated fats and cholesterol , increased intake of fiber foods ^[44] . If significant weight gain is noticed, it is necessary to refer the patient to a nutritionist and a specialist in physiotherapy exercises ^[4] . Caution should be exercised regarding possible symptoms of diabetes (weight loss, drowsiness, thirst, polyuria ). In developing diabetes, it is important to diagnose it as early as possible and begin treatment to prevent the occurrence of life-threatening conditions associated with diabetes ( acidosis and coma ) ^[38] .

It is necessary to regularly monitor the content of transaminases in the blood serum: before starting treatment, every 14 days in the first 4 weeks of treatment, then once a month until the 19th week of treatment, subsequently quarterly. For symptoms of a possible liver disease (e.g., nausea, vomiting, loss of appetite), an analysis of liver samples should be done immediately. In the case of a clinically significant increase in these indicators or the appearance of jaundice symptoms, clozapine therapy should be discontinued. It can only be resumed if the liver function indicators are normalized. In such cases, careful monitoring is required ^[13] .

Due to the possible sedative and hypnotic effect, the drug should not be prescribed to outpatients if they perform work that requires a quick mental and physical reaction (drivers of vehicles , etc. ). Clozapine can slow down the reactivity of patients so much that they are unable to independently be on the street, drive vehicles, service cars , etc.

Patients with a history of primary disorders of the bone marrow, or with a history of heart disease, or with deviations from the cardiovascular system revealed during a medical examination should be prescribed clozapine only when the expected effect of the therapy exceeds the risks ^[13] .

During clozapine therapy, careful monitoring of the condition of patients with epilepsy should be carried out, since there have been reports of dose-dependent paroxysms ^[13] .

Since clozapine can cause sedation and weight gain, it increases the risk of thromboembolism . For this reason, patient immobilization should be avoided ^[13] .

Clozapine has anticholinergic properties that can have undesirable effects on the entire body. Regular examination is necessary with an enlargement of the prostate gland and angle-closure glaucoma . Probably, due to its anticholinergic properties, clozapine can lead to a violation of intestinal motility of varying severity: from constipation to fecal plug, intestinal obstruction and paralytic bowel obstruction. Rarely, these cases can be fatal ^[13] .

С особой осторожностью следует лечить пациентов с наличием в анамнезе заболеваний толстой кишки или хирургического вмешательства в нижней части брюшной полости , получающих сопутствующие препараты, которые наверняка могут стать причиной запора (особенно препараты с антихолинергическими свойствами, например различные нейролептики, антидепрессанты и антипаркинсонические средства), поскольку такие препараты могут ухудшить ситуацию. Чрезвычайно важными являются диагностика и лечение запора ^[13] .

При приёме клозапина не рекомендуется употребление алкоголя ^[34] .

При передозировке клозапина может развиться угнетение сознания вплоть до развития комы , а также симптомы, связанные с холинолитическим действием (тахикардия, делирий), эпилептические припадки, угнетение дыхания, экстрапирамидные нарушения. При приёме дозы, превышающей 2500 мг, существует риск летального исхода ^[25] .

Усиливает центральные эффекты седативных , наркотизирующих, анальгетических , снотворных и противогистаминных средств, алкоголя и ослабляет эффекты леводопы ^[45] . Потенцирует эффекты ингибиторов МАО ^[46] . В сочетании с клозапином препараты, угнетающие ЦНС, алкоголь или трициклические антидепрессанты могут повышать риск развития судорог, седативного или кардиальных эффектов ^[11] .

Всасывание препарата ухудшается при приёме антацидов и холестирамина ^[45] . В свою очередь, клозапин ухудшает всасывание из кишечника антацидов, содержащих ионы алюминия , магния , кальция ^[46] .

Не рекомендуется сочетать клозапин с препаратами, угнетающими лейкопоэз ^[4] (например, карбамазепин ^[4] , пропилтиоурацил, сульфаниламиды ^[11] ), поскольку совместный приём с такими препаратами повышает риск агранулоцитоза ^[4] . Риск агранулоцитоза возрастает также при одновременном приёме с антидепрессантами, повышающими концентрацию клозапина в плазме крови, либо в том случае, если совместно с клозапином применются калийсберегающие мочегонные (например, спиронолактон ) и мочегонные средства тиазидной структуры, ингибиторы ангиотензин-превращающего фермента , нестероидные противовоспалительные препараты ^[47] .

Не следует сочетать клозапин с препаратами, вызывающими запоры и угнетение моторной функции кишечника: например, средствами с холинолитическими свойствами ^[19] ( трициклические антидепрессанты , нейролептики ^[31] ). Необходимо с особой осторожностью сочетать с препаратами, обладающими антигипертензивным эффектом или свойством угнетать дыхание ^[13] .

Одновременный с клозапином приём лития или других препаратов, влияющих на ЦНС, может повысить риск развития злокачественного нейролептического синдрома ^[13] . Сочетание лития с клозапином также повышает риск судорог, спутанности сознания и двигательных расстройств ^[11] .

При применении высоких доз клозапина необходим осторожный подход к сочетанию его с другими диабетогенными препаратами ( бета-адреноблокаторы , глюкокортикоиды , ингибиторы протеаз, тиазидные диуретики ) ^[38] .

При приёме препаратов, ингибирующих изоферменты цитохрома P450 (например, циметидин , кофеин , эритромицин , флувоксамин , флуоксетин , пароксетин , сертралин ), уровень клозапина в сыворотке может существенно возрасти. Вещества, индуцирующие цитохром P450 IA2 (например, фенитоин , никотин , рифампицин ), могут, напротив, уровень клозапина существенно снизить ^[4] .

Сочетание клозапина с циметидином не рекомендуется ^[11] .

Бензодиазепины могут потенцировать токсический эффект клозапина ^[25] . При приёме клозапина в сочетании с бензодиазепинами и другими психоактивными препаратами отмечались случаи остановки дыхания и кровообращения ^[4] . Сочетание с бензодиазепинами может приводить к чрезмерной седации , слюнотечению, атаксии , в некоторых случаях — к расстройству сознания ^[48] ; это сочетание повышает риск развития ортостатического коллапса , обморока ^[11] .

Клозапин ослабляет эффект дофаминергических средств для лечения паркинсонизма ^[46] .

Так как клозапин может снижать судорожный порог, у пациентов, принимающих противоэпилептические средства , может потребоваться коррекция дозы ^[13] . Риск припадков повышается при сочетании клозапина с другими препаратами, снижающими порог судорожной активности (например, флувоксамином или мапротилином ) ^[47] .

При сочетании клозапина с препаратами, обладающими высоким связыванием с белками (например, варфарин и дигоксин ), возможно повышение их плазменных концентраций за счёт их перемещения из белков плазмы крови. При необходимости следует корректировать дозы таких веществ ^[13] .

Синдром отмены клозапина (так называемые холинергические симптомы «отдачи») может развиваться после длительного лечения в дозах свыше 300 мг/сут ^[16] . Риск этого синдрома при отмене данного препарата значительно выше, чем при отмене других нейролептиков. Причины его возникновения: предположительно развитие при приёме нейролептика гиперчувствительности холинергических и дофаминергических рецепторов; задействованы также, по-видимому, серотонинергическая, норадренергическая и ГАМК -ергическая системы. Резкая отмена клозапина допустима лишь при наличии серьёзных клинических показаний и в стационарных условиях; без консультации с врачом и без постепенного снижения дозы (максимум на 50 мг/сут в неделю) отменять препарат нежелательно ^[49] .

Синдром отмены клозапина может включать в себя различную симптоматику, от физического дискомфорта до тяжёлого психоза. При отмене клозапина наблюдались бессонница , беспокойство, возбуждение, дисфория , гиперактивность, агрессия , головная боль , тошнота , рвота , ажитация , синдром беспокойных ног , экстрапирамидные расстройства ( дистонии , дискинезии , тремор ), маниакальные реакции , бред , галлюцинации , делирий , кататония ^{[50] [51] [52] [53] [54]} .

При лечении психозов сверхчувствительности, возникающих вследствие отмены клозапина, желательно применять тиоридазин , который значительно более эффективен в этом случае, чем, например, галоперидол или рисперидон , поскольку обладает сродством к D4-рецепторам ^[55] .

После применения клозапина негативным может оказаться ответ на последующее применение других антипсихотиков, по этой причине пациенты порой становятся практически пожизненно «привязанными» к данному препарату ^[16] .

Негативным следствием снотворной активности клозапина является его притягательность для лиц, страдающих наркоманией, и высокая частота немедицинского потребления этого препарата. Клозапин — единственный из нейролептиков, постоянно перераспределяемый в сферу незаконного оборота психоактивных веществ , в то время как другие антипсихотики обычно вызывают у лиц с наркоманией негативное либо индифферентное отношение ^[56] .

В соответствии с Постановлением Правительства Российской Федерации от 7 ноября 2013 года № 997 клозапин внесён в список сильнодействующих веществ. Незаконный оборот данного препарата влечёт уголовную ответственность согласно статье 234 Уголовного кодекса РФ .

В России клозапин неоднократно использовался преступниками для отравления своих жертв с целью ограбления. Препарат незаметно подмешивали в алкогольные напитки человеку, чтобы тот потерял сознание и появилась возможность для ограбления. Несколько человек погибли из-за передозировки клозапина на фоне употребления алкоголя ^{[57] [58] [59]} .

• Clozapine — описание на сайте MedlinePlus. (eng.)
• Clozapine — описание на сайте eMedTV. (eng.)
• Повторная оценка безопасности применения клозапина при лечении шизофрении