Clozapine: the most effective, but far from safe drug against schizophrenia

Reasons for using the drug in drug addicts

The pronounced sedative, inhibitory effect of Clozapine has long been known among drug addicts. The drug’s ability to enhance the effect of using other types of illegal drugs (depressants) is also used to obtain euphoria. This drug is used much more often than other antipsychotics for recreational purposes.

Clozapine's ability to make it easier to fall asleep is known among drug addicts. They often cannot rest fully at night, and widely use this antipsychotic to eliminate insomnia. In addition to the mixture, underground manufacturers of synthetic substances may use Azaleptin or another type of antipsychotic to potentiate the effect. They care little about the consumer's health; making a profit is much more important to them.

In terms of the degree of anticholinergic effect on the body, Clozapine is often compared with Tropicamide. The latter remedy comes in the form of drops and is considered by many as a cheap type of drug. Since 2013, Azaleptin has been included in the list of potent drugs in the Russian Federation. Its sale without a special prescription form is prohibited by law.

Clozapine: the most effective, but far from safe drug against schizophrenia

Short

A New Zealand study assessing colonic transit time (CTT) using radiopaque markers found that patients treated with clozapine had a median CTT of 104.5 hours - versus 23 hours for those treated with other antipsychotics such as olanzapine, risperidone (risperidone), paliperidone, aripiprazole, zuclopenthixol, haloperidol. Clozapine resulted in a more than fourfold slowing of CTT (p<0.0001), regardless of sex, age, race, duration of therapy, or total drug dose, but with a positive correlation with clozapine plasma levels. In 80% of subjects in the clozapine group, abnormally long CTT was noted in the ascending and descending colon and its rectosigmoid region, which indicates total intestinal hypokinesia. Worse, patients often did not show any subjective symptoms associated with constipation.

Monitoring bowel function and proactive use of laxatives in patients on clozapine therapy has been shown to improve colonic transit time and reduce the risk of serious sequelae.

Clozapine, the originator of atypical antipsychotics as a class of drugs, was introduced in Switzerland and Austria in 1972 under the name Leponex, and entered the US market only in February 1990 under the brand name Clozaril. Clozapine has long been relegated to the category of generic drugs and is known under the following trade names:

• A: Azaleprol, Azaleptin, Azaleptine, Azaleptol, Iqra, Ihope, Alemoxan, Anzapine Anzapine).

• In: Versacloz.

• G: Glipin.

• D: Denzapine, Dicomex.

• Z: “Zaclo”, “Zapine”, “Zapenia” (Zapenia), “Zapine”, “Zaponex”, “Zaporil”, “Ziproc” , "Zopin" (Zopin).

• K: Carapine, Clozabrain, Clozamed, Clozapex, Clozapina, Clozapinum, Klozapol , “Clozarem”, “Clozaril”, “Clozasten”, “Clomach”, “Cloment”, “Clonex”, “Clopaz”, "Clopizam", "Clopin" (Clopin, Clopine), "Clopsine", "Clorazem", "Cloril", "Clorilex", "CloSyn" , "Xenopal" (Xenopal), "Xenopalan" (Xenopalan).

• L: "Lanolept", "Lapenax", "Lepizor", "Leponex", "Lodux", "Lozapin", "Lozapine", "Lozatrik" ( Lozatric), “Lozep”, “Luverina”, “Luften”

• M: Medazepine, Mezapin.

• N: “Nemea”, “Nirva”.

• A: “Ozadep”, “Ozapim”.

• P: “Pinazan”.

• R: “Refraxol”, “Refract”.

• With: "Syzopin", "Syclop", "Sanosen", "Sequax", "Sensipin", "Sizopin", "Sizoril" , “Sicozapina”, “Skizoril”.

• T: “Tanyl”, “Tolanz”.

• U: “Assumption” (Uspen).

• F: FazaClo, Froidir.

• X: Chlorpromazine, Chrozap.

• Sh: "Schizonex" (Schizonex).

• E: Excloza, Elcrit.

Withdrawal syndrome

The drug has the property of being addictive. For this reason, in patients it is withdrawn slowly, gradually reducing the dose over several weeks. If a drug addict cannot take another dose for a certain reason, this leads to a strong withdrawal syndrome. It is accompanied by the following symptoms:

• irritability and aggression
• hypermobility
• tremors and convulsions
• hallucinations (most often visual, but can also be auditory)
• delirium and clouding of consciousness

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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AZALEPTINE (tablets)

sleep disturbances if other medications do not help.
Of course, as always, there are a lot of side effects. Reviews about the drug are mostly negative. They were written by patients who took the drug for a long time and became dependent on Azaleptin. The reviews are simply terrible. So I was in no hurry to buy the drug. I consulted with several other specialists who convinced me that I should at least try. The fact is that with constant insomnia, the body does not rest and is therefore in a state of constant stress. The goal of Azaleptin is to help the body relax and unwind. As the psychologist explained to me, the drug promotes muscle relaxation. In addition, it has a strong sedative, that is, hypnotic effect. Plus, this antipsychotic drug can have a relaxing effect on brain cells and help the body get out of depression or prevent it. In general, I decided to buy it. A jar contains 50 tablets of 25 mg each, costing 270 rubles. I was prescribed 1/2 tablet. Pale yellow tablets. Easily broken in half.

The doctor said that after taking the pill, go straight to bed. But, of course, I was interested in how my body would react. That's why I didn't go to bed. I listened to my feelings for two hours. After a while I felt muscle weakness, but it didn’t bother me too much. I didn't feel like falling asleep. But she still lay down. In the morning I came to my senses, realizing that I don’t remember how I fell asleep and slept for 7 hours. I don't even remember if I ever slept like that. I couldn’t get up for a long time. Now I really felt quite a bit of muscle weakness. Fortunately, I conducted the experiment on a weekend night. The next day I took the drug at 8 pm so that all side effects would go away by morning. As a rule, the effect of such drugs lasts about 12 hours. Unfortunately, the second dose of the drug did not give such a hypnotic effect. I slept for 4 hours. But that wasn't bad either. In the morning there was practically no muscle weakness. On the third day, “Azaliptin”, unfortunately, did not help me fall asleep. It is unlikely that in three days it is possible for the body to get used to the drug, but nevertheless, there was no hypnotic result. And muscle weakness was no longer observed. The same thing was observed a week later.

You can, of course, increase the dose and experiment further, but the drug is very serious and I, like everyone else, am afraid of developing an addiction to it. Moreover, the higher the dose, the greater the likelihood of side effects. So I didn’t increase the dose. My doctor and I decided that I would take the drug once a week so that I could sleep at least on weekends. However, the coveted dose of the drug on the weekend did not give the desired result. But I’m still in no hurry to throw it away. The shelf life allows you to store the drug for a long time, which means that over time you can try treatment with it again. Of course, thinking about whether to recommend this drug or not, I come to the conclusion that I will put “yes”, based on the considerations that it can really help someone.