Treatment of schizophrenia

Neuroleptics are the main class of drugs for the treatment of schizophrenia. They are divided into two main categories: typical neuroleptics, and atypical antipsychotics. The pharmacological properties, including side effects, of each of these categories of drugs are discussed below.

Treatment of schizophrenia with typical antipsychotics

The treatment of schizophrenia began in 1952 with the discovery of the antipsychotic properties of chlorpromazine (Delay and Deniker, 1952). After the efficacy of chlorpromazine was proven in a multicenter, double-blind, placebo-controlled clinical trial, new drugs began to appear for the treatment of schizophrenia. These substances, related to typical (traditional) neuroleptics, are divided into five groups.

There are the following typical neuroleptics:

• Phenothiazines
• Aliphatic (for example, chlorpromazine)
• Piperazine (eg, lerfenazine, trifluoperanein, fluphenazine)
• Piperidinoye (e.g., thioridazine)
• Bugropenones (for example, haloperidol)
• Thioxanthenes (for example, thiotixen)
• Dibenzoxazepines (e.g., loxapine)
• Dihydroindolones (e.g., molindone)

Mechanism of action

The antipsychotic effect of all neuroleptics, with the exception of clozapine, is closely correlated with their ability to block dopamine D2 receptors. Dopamine D2 receptors are localized in the basal ganglia, the contiguous nucleus, and the frontal cortex, where they play a leading role in regulating the flow of information between the cortex of the large hemispheres and the thalamus. Thus, typical neuroleptics can help restore the homeostasis of this system. It is assumed that at the cellular level, typical neuroleptics act by blocking the depolarization of nigrostriral (cell group A9) and mesolimbic (cell group A10) dopaminergic neurons. But the curative effect appears before the blockade of depolarization sets in, and in this connection it is assumed that this physiological effect may prevent the development of tolerance to neuroleptics. The ability of dopaminomimetic drugs, such as amphetamine, methylphenidate, L-DOPA, to induce paranoid psychosis similar to schizophrenia, is an additional argument in favor of the assumption that the dopaminergic system plays a key role in the mechanism of action of neuroleptics. But, given the lack of connection between the metabolism of dopamine and the response to neuroleptics, as well as the resistance of some patients to typical neuroleptics, it can be concluded that dopaminergic activity is only one of the possible factors involved in the pathogenesis of schizophrenia.

Typical neuroleptics to some extent affect other receptors: serotonin (5-HT1C and 5-HT2A), muscarinic, alpha and beta-adrenoreceptors, as well as dopamine D1, D3 and D4 receptors. Clozapine and the neuroleptics of the new generation have a higher affinity for some of these receptors than dofaminovym D2-receptors.

Side Effects of Typical Neuroleptics

Typical antipsychotics cause a wide range of side effects. When using high-potential neuroleptics such as fluphenazine and haloperidol, extrapyramidal disorders are more likely to occur, while low-potential antipsychotics, such as chlorpromazine or thioridazine, more often cause drowsiness and orthostatic hypotension.

The spectrum of side effects in each of the drugs depends on the characteristics of its pharmacological action. Thus, antipsychotics with a more severe anticholinergic effect more often cause disruption of accommodation, constipation, dry mouth, urinary retention. The sedative effect is more typical of drugs with a pronounced antihistamine effect, and orthostatic hypotension - drugs that block alpha 1-adrenergic receptors. To the effects associated with the blockade of histamine and alpha1-adrenergic receptors, tolerance usually develops. Blockade with neuroleptics of cholinergic, noradrenergic or dopaminergic transmission can cause a number of disorders in the genital area, including amenorrhea or dysmenorrhea, anorgasmia, disruption of lubrication, galactorrhea, swelling and tenderness of the mammary glands, a decrease in potency. Side effects in the genital area are mainly explained by the cholino- and adrenoblocking properties of these drugs, as well as an increase in prolactin secretion due to blockade of dopamine receptors.

The most serious side effects are associated with the effect of typical neuroleptics on motor functions. They are the most frequent reason for refusing to take the drug. The three main side effects associated with the impact on the motor sphere include early extrapyramidal disorders, tardive dyskinesia and malignant neuroleptic syndrome.

Major side effects

Central nervous system

• Violation of thermoregulation
• Extrapyramidal disorders
• Malignant neuroleptic syndrome
• Drowsiness
• Epileptic seizures

The cardiovascular system

• ECG changes
• Orthostatic hypotension
• Tachycardia
• "Pirouette" tachycardia

Leather

• Allergic reactions
• Increased skin photosensitivity

Endocrine glands

• Amenorrhea
• Galactorrhea
• Sexual dysfunction
• Weight gain

Gastrointestinal tract

• Cholestatic jaundice
• Constipation

Blood System

• Agranulocytosis
• Leukopenia

Eyes

• Violation of accommodation
• Pigmented retinitis

Urinary system

• Retention of urine

Early extrapyramidal syndromes

The early extrapyramidal syndromes include parkinsonism, dystonia, and akathisia. Parkinsonian symptoms (masklike face, akinesia, restless tremor, rigidity) are associated, it is believed, with the blockade of dopamine D2-receptors in the basal ganglia. These symptoms occur soon after the start of taking the neuroleptic and in the absence of correction can persist for a long time. They are important to distinguish from externally similar negative symptoms of schizophrenia, such as emotional alienation, dulling affect and apathy. To correct parkinsonic symptoms, a cholinolytics (for example, benzotropin or trihexyphenidyl) is prescribed, a dose of neuroleptic is reduced, or it is replaced with a new generation drug.

An acute dystonic reaction is usually manifested by abrupt contractions of the muscles of the face, neck or trunk, for example, a torticollis, an oculogic crisis or opisthotonus. Like parkinsonism, an acute dystonic reaction usually occurs for the first time in days of treatment. As a rule, it is well treatable by intramuscular injection of diphenylhydramine or benzotropin. Late dystonia usually involves the muscles of the neck and, unlike an acute dystonic reaction, is less treatable by anticholinergics.

Akathisia is characterized by a sense of inner anxiety and the need to move (for example, going back and forth) and also usually appears at the beginning of the treatment. Although akathisia can develop along with other extrapyramidal disorders, it often manifests itself in isolation. Akathisia is difficult to tolerate by patients and may be the cause of aggressive behavior or suicidal attempts.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]

Late dyskinesia

Late dyskinesia (PD) manifests involuntary movements that can involve any muscle group, but most often the muscles of the tongue and mouth. In the first 8 years of treatment with neuroleptic PD appears in about 3-5% of patients. It has been established that at least 20-25% of young and middle-aged patients treated with typical neuroleptics develop at least mild manifestations of PD, and in elderly people its prevalence is even higher. Late dyskinesia, as a rule, is a complication of prolonged use of typical neuroleptics, and the duration of therapy is the main risk factor for its development. However, cases have been described where manifestations of PD have occurred in patients who have not been treated for schizophrenia. PD often develops in elderly women and patients with affective disorders. It is suggested that PD is caused by an increase in the number of dopamine receptors in the striatum, although GABA-ergic and other neurotransmitter systems may also be involved in its pathogenesis. Degree of expression PD is variable, but in most cases it is easy. In severe cases PD is able to disable the patient and is often irreversible.

Although a number of methods and methods are proposed for the treatment of PD, there is no universally effective therapy for PD. It is suggested that vitamin E can have a moderate effect in this condition. The most effective measure with PD is a decrease in the dose of neuroleptic, however this is not always possible. Therefore, a moderate or severe PD can serve as an indication for switching to the use of clozapine or another atypical antipsychotic.

Malignant neuroleptic syndrome

Malignant neuroleptic syndrome (CNS) is a rare life-threatening complication of neuroleptic therapy. It is manifested by rigidity of muscles, hyperthermia, vegetative disorders, changes in mental status. With ZNS, leukocytosis and increased activity of creatine phosphokinase (CKF) in the serum are detected. This condition can lead to rhabdomyolysis and acute renal failure. Risk factors for NSA include infections, dehydration, physical exhaustion, child or elderly age, rapid change in the dose of neuroleptic. The frequency of the ZNS is 0.5-1.0%.

The pathogenesis of this syndrome is not clear, but it is suggested that it develops as a result of excessive blockade of dopamine receptors and a decrease in the activity of the dopaminergic system. ZNS should be differentiated with stroke, febrile catatonia and malignant hyperthermia.

Malignant neuroleptic syndrome is an acute emergency that requires urgent hospitalization and infusion therapy. Any antipsychotic medication prescribed to the patient should be canceled. In some cases, dopamine receptor agonists (eg, bromocriptine), amantadine or muscle relaxants (eg, dantrolene) have a positive effect, but their effectiveness has not been systematically studied. In the treatment of NSA, the most important are adequate hydration and symptomatic therapy. After the resolution of the episode, the NSA should not resume taking neuroleptics for at least two weeks. In the future, it is possible to prescribe a low-potential neuroleptic or a new generation drug, less likely to cause extrapyramidal side effects. The dose of the newly prescribed drug should be increased gradually, regularly monitoring the status of vital functions, the level of leukocytes and blood CK.

Toxicity of typical antipsychotics

Typical neuroleptics relatively rarely cause deadly complications. Manifestations of drug overdose mainly depend on their anti-adrenergic and anticholinergic action. Since neuroleptics have a strong antiemetic effect, to remove the drug from the body it is advisable to wash the stomach, and not the appointment of emetics. Arterial hypotension, as a rule, is a consequence of the blockade of alpha1-adrenergic receptors, it should be corrected by the administration of dopamine and norepinephrine. If the heart rate is disturbed, the purpose of lidocaine is indicated. An overdose of an antipsychotic with prolonged action requires cardiomonitoring for several days.

Treatment of schizophrenia with clozapine

Clozapine - dibenzodiazepine, first synthesized in 1959. In the pharmaceutical market in Europe, it appeared in the 60s and was almost immediately recognized as more effective than the typical antipsychotics. But in 1975 in Finland, eight patients died due to infectious complications arising from clozapine-induced agranulocytosis.

As a result, the use of clozapine was limited, and it was prescribed only to individual patients in whom other drugs were ineffective. The successful use of clozapine in this category of patients has prompted a multicentre study in the United States to find out whether clozapine is indeed more effective than typical antipsychotics in resistant patients. After receiving positive results in 1990, clozapine was approved by the FDA (Food and Drug Administration) for use in the United States. The drug was allowed to be used in the resistance of positive symptoms to typical neuroleptics or with their intolerance. Clozapine - the only drug whose advantage over typical antipsychotics in resistant to schizophrenia is firmly established. In addition, it facilitates displays of hostility and aggressiveness, tardive dyskinesia, and also reduces the risk of suicide.

The mechanism of action of clozapine

Clozapine modulates the activity of a number of neurotransmitter systems. It is an antagonist of both D1- and D2-dopamine receptors. But unlike typical neuroleptics, clozapine has the greatest affinity for the EM receptor, and its affinity for D1 receptors is higher than for D2 receptors. In addition, clozapine is a potent blocker of serotonin receptors, its affinity for 5-HT2a receptors is higher than for any types of dopamine receptors. Clozapine also blocks serotonin 5-HT2Ca, 5-HT6- and 5-HT7 receptors, alpha1 and alpha2-adrenoreceptors, cholinergic receptors (both nicotinic and muscarinic), as well as histamine (H1) receptors.

From the typical neuroleptics, clozapine is distinguished by a number of other properties. In laboratory animals, clozapine does not cause catalepsy, does not block the stereotypes caused by apomorphine or amphetamine, does not increase serum prolactin levels and the sensitivity of dopamine receptors. In addition, clozapine blocks the depolapization of only A10-dopamine neurons, consistent with the data obtained in assessing clozapine-induced enhancement of c-fos protein expression. Clozapine enhances the expression of c-fos (a new marker of cellular activity) in the contiguous nucleus, ventral part of the striatum, anterior cingulate and medial prefrontal cortical areas. Unlike clozapine, haloperidol activates the expression of c-fos in structures innervated by dopaminergic neurons belonging to group A9, for example, in the dorsal striatum. But up to the present time it remains unclear what exactly is the pharmacological properties of clozapine due to such high antipsychotic activity.

Side effects of clozapine

Despite its high effectiveness, clozapine is used in a limited way due to the danger of some side effects, although in many respects this drug is safer than other antipsychotics. In comparison with typical neuroleptics, clozapine very rarely causes early or late extrapyramidal complications. When clozapine is used, there is rarely Parkinsonism or akathisia, and cases of acute dystonic reaction are not described at all. In addition, it is suggested that clozapine does not cause tardive dyskinesia; although several similar cases have been described, their association with clozapine has remained unclear. Moreover, there was a correlation between a wide spread of the drug and a decrease in the incidence of tardive dyskinesia. It also turned out that clozapine can be used to treat late dystonia and severe akathisia. Due to the low risk of malignant neuroleptic syndrome, clozapine should be considered as a drug of choice in patients who have experienced this complication before.

Nevertheless, with clozapine, a number of serious side effects are possible, the most dangerous of which is agranulocytosis, occurring in 0.25-1.0% of patients. Most often it develops within the first 4-18 weeks of therapy, although cases of its occurrence more than a year after the start of treatment are described. Agranulocytosis can develop rapidly or gradually. This complication is more common in elderly women and people taking other drugs that can depress hemopoiesis. The mechanism of development of agranulocytosis is unknown, but it is suggested that it develops due to direct toxic effects, immune response or combined toxic-immune mechanism. There is unconfirmed data on the possible association of haplotype HLA and the increased risk of agranulocytosis. In addition, it is suggested that the closapine metabolite, norclosapine, has a toxic effect on bone marrow cells. According to the recommendations developed by the FDA, a weekly check of blood leukocyte counts is required at the time of taking the drug. The greatest risk of agranulocytosis exists in the first 6 months of treatment, therefore, for longer treatment these recommendations may be revised. Patients should not simultaneously prescribe drugs that suppress bone marrow function, for example, carbamazepine. If the level of white blood cells falls below 2000 / mm ³ (and the granulocyte count is below 1000 / mm ³ ), clozapine should be immediately discontinued and the patient should be hospitalized in an isolator (to prevent infection). At the time of hospitalization, the leukocyte formula should be examined at least every other day. To strengthen the regeneration of granulocytes, you can use filgastrim - the coloniostimulating factor of granulocytes. Patients who developed agranulocytosis should not subsequently be assigned clozapine. There are no data that would indicate an increased risk of agranulocytosis under the influence of other drugs in patients with this complication of clozapine treatment.

Among the other important side effects that can occur with clozapine are drowsiness, hypersalivation and weight gain, which is usually increased by the time the clozapine is administered under the influence of previous antipsychotic therapy. Side effects such as tachycardia, orthostatic hypotension and epileptic seizures should also be mentioned. The risk of developing generalized convulsive seizures with clozapine is relatively high (up to 10%); in addition, it can provoke myoclonic and atonic paroxysms. Myoclonic twitching often precedes the development of a generalized convulsive fit. The probability of changes in electroencephalography (EEG) and the occurrence of seizures depends on the dose. Their risk significantly increases if the dose of clozapine exceeds 600 mg / day. The development of seizures is not a contraindication to the further use of clozapine, but requires a dose reduction of the drug to half the last dose that did not cause seizures. In addition, the use of antiepileptic drugs such as valproic acid should be considered. Carbamazepine should not be prescribed because of the risk of agranulocytosis.

The toxicity of clozapine

With an overdose of clozapine, depression of consciousness is possible up to the development of coma, as well as symptoms associated with holinolitic action (tachycardia, delirium), epileptic seizures, respiratory depression, extrapyramidal disorders. When taking a dose exceeding 2500 mg, a fatal outcome may occur.

The high efficacy of clozapine with a low risk of extrapyramidal disorders was the impetus to develop a new generation of antipsychotics. These drugs were given one or more pharmacological properties - the characteristics of clozapine in order to obtain an equally effective remedy, in which the risk of extrapyramidal disorders and agranulocytosis would be minimized. Although new antipsychotics have surpassed clozapine in safety, until now it has not been possible to create a drug that would not be inferior to clozapine in effectiveness (Conley, 1997). Clozapine and new generation drugs are called atypical, taking into account the peculiarities of their pharmacological action and the rarity of extrapyramidal complications.

Manifestations of an overdose of clozapine

• Severe extrapyramidal disorders (including distonnya and severe muscular rigidity), drowsiness
• Mydriasis, reduction of deep tendon reflexes
• Tachycardia (low-potential neuroleptics); arterial hypotension (blockade of alpha-adrenergic receptors in the absence of action on beta-adrenergic receptors)
• EEP diffuse slow low-amplitude waves; epileptic seizures (low-potential neuroleptics)
• Elongation of the interval QT; atypical ventricular ("pirouette") tachycardia with a secondary conduction block or ventricular fibrillation

Treatment of schizophrenia with risperidopom

Risperidone has been used since 1994. Risperidone is a benzisoxazole derivative with a high affinity for 5-HT2a and dopamine D2 receptors, and it blocks more serotonin than dopamine receptors. In addition, risperidone effectively blocks alpha 1-adrenergic receptors and histamine H1 receptors, but is less active against alpha2-adrenergic receptors. The drug has no significant effect on dopamine D1 receptors and cholinergic receptors. Like typical antipsychotics, risperidone blocks depolarization of dopamine neurons related to both A9 and A10 groups, and in high doses causes catalepsy and muscular dystonia in experimental animals.

These pharmacological properties of risperidone are reflected in the spectrum of side effects. The risk of developing parkinsonism depends on the dose - usually parkinsonian symptoms become pronounced with a dose of at least 10 mg / day. Reported cases of PD and ZNS that occurred during treatment with risperidone, but the relative risk of PD when taking this drug (compared with typical neuroleptics) is not clearly established. Other side effects include nausea, vomiting, agitation, anxiety, insomnia, drowsiness, increased prolactin levels in the serum, weight gain. But, in general, risperidone is relatively well tolerated.

In case of an overdose, somnolence, epileptic seizures, prolongation of the QT interval and expansion of the QRS complex, arterial hypotension, extrapyramidal disorders are possible. Deaths caused by an overdose of risperidone are described.

Treatment with olanzapine

Olanzapine has been used to treat schizophrenia since 1996. According to the spectrum of pharmacological action, it is very close to clozapine - olanzapine effectively blocks dopamine (both D1 and D2), as well as serotonin (5-HT2A, 5-HT2C, 5-HT6) receptors, alpha1-adrenoreceptors, histamine (H1) and muscarinic (M1) receptors. But, unlike clozapine, it has relatively little effect on serotonin receptors, as well as on alpha2-adrenoreceptors and other cholinergic receptors. Like clozapine, risperidone and other atypical antipsychotics, olanzapine has a higher affinity for 5-HT2A receptors than for dopamine D2 receptors. Like clozapine, it blocks the depolarization of dopaminergic neurons of the A10 group, but not of the A9 group. Catalepsy and dystonia in experimental animals cause only high doses of the drug.

Due to its pharmacological properties, olanzapine, even when used in high doses, is much less likely to cause extrapyramidal side effects than typical neuroleptics. In addition, olanzapine has virtually no effect on prolactin levels in the blood and, apparently, does not cause any side effects from the cardiovascular system, including tachycardia. However, olanzapine can cause drowsiness, dizziness, dry mouth, constipation, moderate weight gain.

In case of an overdose, a sedative effect, toxic cholinergic action (including tachycardia and delirium), epileptic seizures, arterial hypotension, extrapyramidal disorders are possible. To date, there is insufficient data to assess the risk of death in overdose.

Treatment with coutnapine 

Quetiapine weakly blocks dopamine D1 and D2 receptors, as well as serotonin 5-HT2a and 5-HT1c receptors, but its affinity for 5-HT2a receptors is higher than for dopamine D2 receptors. In addition, it is able to block alpha1 and alpha2-adrenergic receptors, but does not show anticholinergic properties. Quetiapine does not lead to activation of c-fos in the dorsal striatum and in therapeutic doses does not cause catalepsy and dystonia in experimental animals. Against the background of taking quetiapine, there are no significant extrapyramidal disorders, including akathisia. However, it can cause drowsiness, headache, transient increase in the level of hepatic transaminases, increase in body weight. Quetiapine does not cause an increase in the level of prolactin in the plasma.

Treatment with ziprasidone

Ziprasidone has a unique profile of pharmacological action. Being a potent antagonist of 5-HT2a and dopamine D2 receptors, ziprasidone is also an active inhibitor of reuptake of serotonin and norepinephrine. Although ziprasidone blocks depolarization not only of A9-, but of A10-dopaminergic neurons, in experimental animals it is capable of producing only catalepsy in large doses. Against the background of ziprasidone, there were no extrapyramidal side effects.

Currently, at the early stage of development is still a number of new antipsychotics. Next generation drugs may have a different mechanism of action (for example, they will be partial agonists of the glycine site of the NMDA receptor complex) and will be able to influence various manifestations of schizophrenia, including negative symptoms.

Treatment of the first psychotic episode

At the first psychotic episode, and also in case when treatment was not spent more than 1 year therapy it is expedient to begin with a neuroleptic of new generation. To date, the drugs of choice include risperidone, olanzapine, quetiapine and sertindole. Risperidone is recommended to appoint a dose of 1-4 mg once a day (before bedtime), the maximum dose is 6 mg / day. Treatment with olanzapine should be started with a dose of 10 mg once a day (before bedtime), then if necessary, it is increased to 20-25 mg / day during a week. Sertindole is initially prescribed in a dose of 12 mg once a day, then it is increased to 20-24 mg (the entire dose is taken only once before bedtime). Treatment with quetiapine begins with a dose of 75 mg, then it is increased to 150-300 mg 2 times a day (daily dose is 300-600 mg / day).

The initial stage of treatment lasts three weeks. With a good response to treatment and in the absence of complications, taking the drug at an effective dose continues for 6-12 months. At this point, the need for further antipsychotic therapy should be assessed. During this time in newly emerged cases it is possible to clarify the diagnosis. In the chronic course of schizophrenia, it is likely that long-term maintenance therapy will be required.

If previously a typical neuroleptic was prescribed to the patient, which was effective and well tolerated, then the drug should be resumed. Of the typical antipsychotics, most often use haloperidol (5-15 mg / day) and fluphenazine (4-15 mg / day), which in these doses, as a rule, do not cause serious side effects. Patients who were previously helped with drugs with a weaker antipsychotic effect (for example, perphenazine or chlorpromazine), you can reassign these same remedies. Due to the high risk of extrapyramidal side effects, typical neuroleptics are not currently considered as first-choice drugs in patients with newly diagnosed schizophrenia.

Treatment of agitation and insomnia

Often immediately after hospitalization, patients are noted for excitement and hostility. Usually excitation can be relaxed by placing the patient in a calm, controlled environment. In addition to calming the patient, lorazepam (0.5-2 mg) with anxiolytic and hypnotic action can be prescribed. Lorazepam is usually used for a short time, necessary for the normalization of the patient's behavior. Most patients respond favorably to a calm and measured situation, the need for lorazepam is maintained only for 1-2 days. If short-acting benzodiazepines are contraindicated, antipsychotics are used to suppress excitement in a relatively high dose-for example, haloperidol (1-5 mg or 1-2 mg intramuscularly) or droperidol (1-2 mg intramuscularly). These drugs should be referred to as reserve drugs because of the possibility of developing extrapyramidal disorders, including dystonia. Droperidol should be administered only if there are conditions for an emergency correction of possible cardiovascular dysfunction, since this drug, although rare, can cause a life-threatening collapse. Just like lorazepam, these drugs are prescribed for a limited period (the first 1-2 days of hospitalization).

The second complication of an acute psychotic episode, which often requires correction, is sleep disturbance. The drug of choice in this case are benzodiazepines (for example, lorazepam). If they are contraindicated, diphenylhydramine or chloral hydrate may be used as a hypnotic. The use of sleeping pills should also be limited in time, as within 1-2 weeks after the onset of an acute psychotic episode, sleep usually normalizes.

Treatment of extrapyramidal disorders

Extrapyramidal disorders are one of the most serious complications of neuroleptic therapy. They can be represented by the symptoms of parkinsonism, akathisia and dystonia, appearing quickly or gradually. With the use of neuroleptics of a new generation, the likelihood of developing drug parkinsonism is minimized. However, only clozapine, being an effective antipsychotic, almost never causes parkinsonism. Nevertheless, because of the danger of agranulocytosis, it is not recommended to use it as a drug of the first choice. Other atypical antipsychotics (risperidone, olanzapine, sertindole, and quetiapine), although less likely to cause extrapyramidal disorders than typical neuroleptics, are still capable of causing parkinsonism, especially in high doses. Therefore, when using these drugs, it is important not to exceed the usually recommended dose and regularly monitor the condition of patients.

One of the most important advantages of atypical neuroleptics is that the symptoms of drug parkinsonism can be eliminated by lowering the dose of the drug without sacrificing the antipsychotic effect. If the growing symptoms of Parkinsonism significantly limit the vital activity of the patient, then for their correction should be appointed high-speed antiparkinsonian drugs, for example, diphenhydramine or benzotropin. Their use also reduces the likelihood of an acute dystonic reaction. Nevertheless, the main method for correcting the symptoms of parkinsonism in a patient taking an atypical neuroleptic is to reduce the dose of the drug, and an antiparkinsonian remedy is prescribed only for a limited time.

Parkinsonism, which developed against the background of taking typical neuroleptics, is usually more pronounced and persistent. In this case, the main method of its correction is also a decrease in the dose of neuroleptic, which in most cases brings the necessary effect. An antiparkinsonian drug may be useful, but, if possible, it should be used only in acute situations. If parkinsonism or another extrapyramidal side effect developed against a background of long-term use of a typical neuroleptic and does not decrease with a decrease in its dose, then it is necessary to switch to the atypical neuroleptic. If persistent parkinsonism has developed in the treatment of atypical neuroleptics, then you should switch to taking another drug from the same group. If these measures proved ineffective, then you can designate clozapine.

Treatment of akathisia

Akathisia can be combined with other extrapyramidal syndromes. Akathisia is caused by both atypical and typical neuroleptics. Correction of this complication is carried out by lowering the dose of neuroleptic and additional appointment of beta-blockers. In some cases, it is necessary to change the drug to a neuroleptic of another class. Clozapine can reduce akathisia, resistant to other methods of treatment.

Supportive treatment of schizophrenia

After regression of symptoms and stabilization of the patient's condition, long-term maintenance therapy is conducted in order to prevent the intensification of symptoms or the development of a new exacerbation. Treatment at this stage is usually performed on an outpatient basis, so it is important to minimize side effects and achieve accurate follow-up of patient treatment recommendations. In this phase of treatment, such aspects as the quality of life and the economic effectiveness of treatment acquire special significance. Achieving these goals is possible only if effective psychosocial rehabilitation, combined with pharmacotherapy.

Long-term antipsychotic therapy has long been recognized as the most optimal approach to the treatment of most patients with schizophrenia. Controlled studies show that with the use of neuroleptics, exacerbations develop three times less frequently than with placebo. For many years, high doses of antipsychotics (equivalent to 600-1200 mg of chlorpromazine) were used for maintenance therapy. Against the backdrop of this approach, the rate of relapse and re-hospitalization in the 60-80s of the last century decreased, but remained very significant. The effectiveness of the treatment was tried to improve by prescribing very high doses. However, controlled studies have shown the lack of advantages of this tactic. In addition, the appointment of high doses increased the frequency of tardive dyskinesia, and the willingness of patients to cooperate (compliance) was reduced.

To improve compliance, long-acting depot preparations fluphenazine and haloperidol were produced in which the active substance was associated with the lipid decanoate. The drugs are administered intramuscularly. One injection provides a stable level of the drug in the blood for 4 weeks. In clinical trials, depot preparations provided a higher level of relapse prevention than oral agents (Davis et al., 1993). In this regard, many experts believe that depot preparations are not widely used in the US.

It was found that if the dose of neuroleptic exceeds the value equivalent to 375 mg of chlorpromazine, then the effectiveness of maintenance therapy does not increase. In about half of patients, the minimum effective dose is equivalent to approximately 50-150 mg of chlorpromazine. According to current recommendations, the standard maintenance dose should be equivalent to 300-600 mg of chlorpromazine.

In the last decade, various methods have been tried to change the risk-to-benefit ratio of maintenance therapy in a more favorable way. It turned out that with a significant reduction in the maintenance dose, you can reduce the risk of side effects, improve compliance and at the same time maintain a therapeutic effect on most parameters. The results of these studies aroused widespread interest and led to changes in the practice of treatment. With prolonged administration of an antipsychotic at a dose of 10% of the standard, the frequency of exacerbations increased, but the degree of social adaptation of the patient was higher, and the risk of side effects was lower. When the dose was 20% of the standard, the frequency of exacerbations was also higher, but they were less pronounced. And these exacerbations could be treated out-patient, additionally appointing the drug inside. At the same time, other manifestations of the disease, including negative symptoms, also decreased.

Similar results were obtained in the case when patients did not undergo maintenance treatment and only with the first symptoms of relapse started intensive antipsychotic therapy. However, this scheme proved to be more burdensome for both patients and psychiatrists, and its results are not generally as convincing as with maintenance therapy with small doses. In one study, which directly compared the effectiveness of maintenance therapy with standard and small doses and therapy only when symptoms appeared, it was shown that with a constant low dose, the total dose of the drug (during the study period) is less, and the frequency of relapse of the psychotic symptom is lower , than when treating only exacerbations. However, both of these regimens reduced the impact of antipsychotics on the patient and the severity of negative symptoms compared with maintenance therapy with standard doses. Nevertheless, at the end of the two-year study period, the frequency of exacerbations in groups with alternative approaches was higher than in patients who were on maintenance therapy with standard doses, but there were no significant differences in the severity of the psychotic symptomatology.

The above data allow us to formulate the following recommendations.

1. For the majority of patients, long-term maintenance therapy with constant doses of antipsychotic is optimal.
2. Doses of typical neuroleptics should be significantly lower than those taken earlier (600-1000 mg chlorpromazine). Currently, doses of 200-400 mg are accepted, and in many patients doses of 150-300 mg (in chlorpromazine equivalent) are effective.
3. Depot preparations improve the compliance of patients who agree to this type of treatment. The greatest experience of maintenance therapy with low doses was obtained with the use of depot preparations. With the possibility of regular observation of patients, 12.5 mg of fluphenazine decanoate is administered once every 2-3 weeks, and 25-50 mg of haloperidol decanoate - once every 4 weeks, resperidone (const), 25-75 mg - once every 2 weeks . These doses provide the necessary effect in most patients. With a periodic exacerbation of psychosis, an additional prescription of an antipsychotic for several weeks is possible.
4. In patients who refuse long-term administration of antipsychotics, as well as with prolonged remission after a single psychotic episode, therapy is performed only with exacerbation.
5. Persistent side effects are an indication of a dose reduction.
6. The appearance of the first symptoms of tardive dyskinesia is an indication for the abolition of maintenance therapy (with the resumption of neuroleptic medication only with exacerbation of psychosis), a significant reduction in the dose of neuroleptic or its replacement with clozapine.

These recommendations may be revised after the results of studies of supportive therapy with neuroleptics of a new generation appear. Already there is evidence of a higher efficacy of clozapine in preventing exacerbations in chronic patients resistant to typical neuroleptics. The relative risk of extrapyramidal side effects makes it possible to expect that patients will better follow the recommendations of the doctor, and this will improve the effectiveness of treatment. However, with regard to the neuroleptics of the new generation, it is unclear whether their dose reduction allows them to optimize the risk-effectiveness ratio. On the other hand, it is important to compare the results of maintenance therapy with atypical antipsychotics and low doses of typical neuroleptics. Treatment with risperidone at a dose of 4 mg / day will have undoubted advantages over the appointment of haloperidol at a dose of 15-20 mg / day. But it remains unclear whether these advantages will persist if a comparison is made with haloperidol at a dose of 4-6 mg / day or fluphenazine decanoate at a dose of 12.5 mg once every three weeks. The choice of the drug, of course, appears and the ratio of cost and effectiveness.

Resistance to the treatment of schizophrenia

Partial or inadequate treatment effect is one of the most difficult problems of pharmacotherapy of schizophrenia. In the past, to overcome resistance to treatment, the dose was varied or additional agents such as lithium salts, anticonvulsants or benzodiazepines were prescribed. With the advent of clozapine, a new generation of antipsychotics began to be used more widely in the treatment of such patients. This is due to the fact that atypical antipsychotics are more effective or less likely to cause side effects than traditional drugs.

By resistance to therapy is understood the preservation of psychotic symptoms (distorted perception of reality and disorganization of behavior) and associated disorders, despite adequate pharmacotherapy.

Typical antipsychotics

Typical neuroleptics for a long time remained the drugs of choice for the treatment of schizophrenia. By their effectiveness, they are considered to be equivalent. Only one of more than 100 comparative studies found differences in efficacy. In controlled studies, less than 5% of patients resistant to one of the typical antipsychotics succeeded by replacing it with another traditional drug. The choice of the drug was mainly guided by the desire to reduce the risk of side effects and to be able to vary the dose. High-potential agents, such as fluchenazine haloperidol, often cause extrapyramidal side effects, but are less likely to cause drowsiness and orthostatic hypotension than low-potential agents, such as chlorpromazine and thioridazine. Haloperidol and fluphenazine are the only neuroleptics that exist in the form of depot preparations for parenteral administration. They allow to improve compliance and sometimes - to get a more pronounced effect.

The choice of an antipsychotic for a particular patient depends on the effectiveness and tolerability of the drugs that were prescribed to him earlier. In the absence of clinical improvement after three weeks of treatment, it is necessary to check whether the patient should follow the prescribed treatment regimen by measuring the level of the drug in the blood. If the patient conscientiously takes the drug, then in the absence of a noticeable improvement after 4-8 weeks should think about changing the drug.

Atypical antipsychotics

With ineffectiveness of typical neuroleptics, the drugs of choice are atypical antipsychotics. Of this group, four drugs are most commonly used: clozapine, risperidone, olanzapine and quetiapine.

[16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]

Clozapine

It is recommended to be used when, with the help of typical neuroleptics, it is not possible to achieve the desired effect, either because of the low effectiveness of the drug, or because of severe side effects. Clozapine remains the only drug whose ability to overcome resistance to the treatment of schizophrenia, established according to strict criteria, is considered proven.

Despite the significant clinical effectiveness of clozapine, not all patients use it to improve social adaptation and reduce the cost of maintaining patients, especially in the first year of therapy. Part of this can be explained by the fact that clozapine is usually prescribed to patients who are difficult to treat and spend a long time in psychiatric hospitals. In addition, it is used by a limited circle of psychiatrists who are used to working with it. Other studies show that prolonged treatment with clozapine is cost-effective in terms of cost-effectiveness.

The optimal strategy for the application of clozapine is a gradual increase in the dose. The effect can be expected when taking the drug at a dose of 200-600 mg / day. Only with good tolerability of the drug dose can be increased above 600 mg / day. It is not recommended to increase the dose of clozapine with the appearance of myoclonic twitchings, which can serve as precursors of epileptic seizures. In patients responding to clozapine, the improvement usually occurs within 8 weeks after reaching the optimal dose.

[30], [31], [32], [33], [34], [35], [36], [37], [38], [39]

Risperidone

Risperidone effectively suppresses the positive symptoms of schizophrenia. In addition, when prescribing the drug at a dose of up to 6 mg / day, the risk of developing extrapyramidal disorders is not higher than that of placebo. However, in a dose of 10 mg / day or more, the drug causes extrapyramidal disorders, and this side effect is dose-dependent. Thus, low and high doses of risperidone can have a different clinical effect. There is no evidence that high doses of risperidone (8 mg / day or more) are more effective, so for most patients, a dose of 2 to 6 mg / day is considered optimal.

Although there is evidence that risperidone is more effective than haloperidol, the question remains whether it has advantages over typical neuroleptics in the resistance of schizophrenia to treatment established according to clear criteria. Although there have been reports of cases in which risperidone improves the condition of patients who previously did not respond well to treatment, these studies were open or retrospective and were not controlled.

In one of such studies it was shown that in the treatment of chronic patients risperidone is not inferior in effectiveness to clozapine. However, in this work, patients were not divided on the basis of resistance to therapy, moreover, the study was not extensive enough to correctly compare the effectiveness of the two drugs.

It is firmly established that risperidone is ineffective in patients resistant to clozapine. But there are reports of his ability to improve quality of life and reduce the duration of hospitalization in patients who are resistant to therapy. Because risperidone is much safer than clozapine and better tolerated than typical antipsychotics, resistant patients are recommended to prescribe risperidone before switching to clozapine.

Olanzapine

Close to clozapine for pharmacological action and effective in schizophrenia, amenable to treatment with neuroleptics. It rarely causes extrapyramidal disorders than typical neuroleptics, and akathisia when treated with the drug occurs at the same frequency as with placebo. In an open clinical trial, olanzapine was effective in a proportion of patients who were reliably resistant to antipsychotic therapy. However, in a double-blind study, this result could not be confirmed; there was only a decrease in the level of anxiety and depression. In the most effective dose (15-25 mg / day), olanzapine is significantly better tolerated than chlorpromazine. Olanzapine can be prescribed to patients resistant to typical neuroleptics, but it is unlikely that it will significantly improve the status of patients resistant to risperidone.

Quetian

Has a higher affinity for serotonin (5-HT1A) than for dopamine receptors. It is an antipsychotic with a relatively low activity. The greatest effect is in the dose of 300-450 mg / day, like clozapine. The drug is safer than typical neuroleptics, and the likelihood of developing extrapyramidal disorders (including akathisia) when it is used is not higher than that of placebo.

In the case of Vvedepin, patients resistant to therapy, the following points should be borne in mind.

1. Resistance to therapy is determined by the presence of persistent psychotic disorders or other difficult-to-control psychopathological manifestations.
2. Resistance to therapy is a spectrum of conditions, and patients who are absolutely resistant (refractory) to treatment constitute the heaviest part of this spectrum.
3. Clozapine is the most effective antipsychotic drug in patients resistant to therapy.
4. Although the neuroleptics of the new generation are more safe than clozapine and typical antipsychotics, their effectiveness in patients resistant to treatment is not definitively determined.

Treatment of schizophrenia by alternate methods

If the traditional treatment of schizophrenia has not been successful, it should be treated with alternative therapies. These include auxiliary drugs, reserpine and electroconvulsive therapy (ECT). Since the effectiveness of these methods can not be considered proven, they can only be used in certain situations.

Lithium preparations

The addition of the lithium preparation allows some patients with schizophrenia to overcome resistance to treatment. To assess the effectiveness of lithium, a 4-week trial course is sufficient. Although lithium is more effective in patients with affective disorders, its purpose also gives a positive result in other categories of patients. According to some sources, lithium reduces hostility in resistant patients and can be especially useful in stimulation.

Although studies on the effectiveness of lithium (as an auxiliary drug) in patients with resistant schizophrenia have yielded positive results, they were conducted in small groups of patients. Therefore, the effectiveness of lithium can not be considered proven. Be careful to use a combination of lithium with a typical neuroleptic or clozapine because of the risk of delirium and encephalopathy.

Anticonvulsants

Carbamazepine and valproic acid are effective in bipolar affective disorder with psychotic manifestations. However, they are often used as an aid in schizophrenia. Several controlled studies have demonstrated the undoubted efficacy of carbamazepine as an adjuvant in patients with schizophrenia, but a small number of patients have been included in these studies. Positive changes, in general, were moderate and more concerned areas such as behavior and social adaptability. Carbamazepine can not serve as an alternative to neuroleptics, as it can not prevent the recurrence of schizophrenia.

Carbamazepine should be used with caution, as it can cause disorientation, ataxia and agranulocytosis. In addition, carbamazepine is able to reduce the concentration of haloperidol in the blood by about 50%. In view of the danger of toxic hepatitis, care should be taken when administering valproic acid.

[40], [41], [42], [43], [44], [45], [46], [47], [48], [49]

Benzodiazepines

There are several reports of the use of benzodiazepines as an adjuvant in the treatment-resistant schizophrenia. Uneven results were obtained: in some studies with double-blind control, the positive effect of benzodiazepines was shown, in others their use was ineffective. Since patients with schizophrenia often have irritability and anxiety, it is not surprising that they are often prescribed benzodnazepines. But caution should be exercised in prescribing these medications, since their use can lead to permanent drowsiness, fatigue, ataxia, drug dependence, behavioral disinhibition. In addition, benzodnazepines can potentiate the toxic effect of clozapine. Anxiolytics in schizophrenia are used primarily to stop the excitation or treatment of prodromal symptoms (early relapse symptoms) in patients refusing to take antipsychotics.

[50], [51], [52], [53], [54], [55], [56], [57], [58], [59]

Antidepressants

In many patients with schizophrenia during an acute episode, there are manifestations of depression, and in the chronic phase they are often demoralized. Neuroleptics can aggravate the symptoms of depression. In the past, antidepressants were rarely used in schizophrenia, for fear that they could provoke psychosis. The probability of this, apparently, is insignificant. In general, the effectiveness of antidepressants in most patients with schizophrenia is very moderate, they do not eliminate the state of demoralization. Nevertheless, patients with persistent depression or a depressive episode arising separately from psychotic disorders should be prescribed antidepressants in the lowest effective doses. There is evidence of the ability of clozapine to positively influence the depressed mood and reduce the risk of suicide.

[60], [61], [62], [63], [64], [65], [66], [67]

Other treatments for schizophrenia

Although several studies conducted in previous years have shown a positive effect of beta-blockers and reserpine in the treatment-resistant schizophrenia, controlled trials of these drugs using modern diagnostic criteria have not been conducted. Thus, there is practically no evidence of the effectiveness of long-term therapy with at least one of these drugs.

Controlled trials of ECT in treatment-resistant schizophrenia have also not been conducted. Before the introduction of clozapine, several studies of ECT have been conducted, which showed that it can be effective in patients resistant to drug therapy, although this effect was more pronounced in patients with a small prescription of the disease. Two open studies have shown that ECT can have some positive effect in patients resistant to cllozapine. However, the stability of the result obtained and the long-term effectiveness of ECT were not reported.

To increase the effectiveness of antipsychotic pharmacotherapy, the following principles should be followed.

1. Exact definition of the therapeutic target - symptoms, the correction of which will be directed to treatment. Neuroleptics are more effective in treating positive symptoms of schizophrenia, which include hallucinations, delusions, thinking disorders and inadequate behavior. Drugs of the new generation can also affect negative symptoms, such as social isolation, isolation and dulling of affect, especially if they are caused by typical neuroleptics. Clozapine is especially effective in the treatment of hostile, aggressive patients with psychosis. The choice of a therapeutic target makes it possible to more clearly evaluate the effectiveness of the drug.
2. Evaluation of the effectiveness of the antipsychotic is possible only after its appointment in optimal doses for a sufficiently long time. This rule is particularly important to comply with the inclusion in the treatment regimen of ancillary drugs. Otherwise, in the future, there may be insurmountable difficulties in the selection of optimal therapy. Typical antipsychotics are often prescribed at too high a dose, which negatively affects the effectiveness of treatment (even with acute psychosis) due to side effects and low compliance of patients.
3. It should be borne in mind that the reason for the apparent resistance to treatment may be poor drug tolerance, non-compliance with the treatment scheme (noncompliance). Inadequate social support or lack of psychosocial care can create the appearance of resistance to treatment. Therefore, before recognizing a particular drug ineffective, you should exclude these factors. Although for most antipsychotics the range of therapeutic doses is not exactly established, measuring the concentration of the drug in the blood can be helpful, since it helps to check whether the patient regularly takes the drug.
4. It is necessary to accurately assess the effectiveness of monotherapy with one or another drug before proceeding to a combination of drugs. The doctor often tries (sometimes under external pressure) to pick up such treatment, which would quickly save the patient from all his psychopathological manifestations. But it should be remembered that the ability to enhance the effectiveness of neuroleptic therapy has not been proven for any of the aids. Hostility, irritability, insomnia, isolation can be a consequence of psychosis and can regress only against the background of successful antipsychotic therapy.
5. The choice of the drug is carried out taking into account the risk of extrapyramidal side effects. Neuroleptics of the new generation are effective in doses that do not cause extrapyramidal complications in most patients. This avoids persistent side effects, which are the reason for the low effectiveness of treatment.
6. It is important to maintain a positive therapeutic attitude. Every year, the choice of antipsychotics is becoming more widespread. It is necessary to support the patient in the belief that even with the most severe mental illness, an effective treatment will be found.
7. It should pay maximum attention to socio-psychological factors, protecting the patient from stress, contributing to an adequate understanding of the disease and his family nature of the disease - this significantly increases the effectiveness of treatment.

Atypical antipsychotics have a different mechanism of action than typical drugs, so doctors should make the most of the special effects of different groups of drugs, trying to help patients who are resistant to therapy. To date, clozapine - the only drug that can overcome therapeutic resistance. Determine the effectiveness of other new generation drugs in the treatment of schizophrenia, resistant to therapy, should be in well-planned studies with double-blind control and the application of clear criteria for selecting patients.

Elimination of negative symptoms of schizophrenia

Although in most cases of therapeutic resistance the emphasis is on the persistence of positive symptoms, the importance of problems associated with persistent negative symptoms is increasingly recognized. In studies with double-blind control, clozapine and other new generation antipsychotics (risperidone, olanzapine, quetiapine) have been shown to work more effectively on negative symptoms than typical neuroleptics. But it remains unclear whether these drugs directly affect the primary negative symptoms of schizophrenia, or whether this effect is due to the weakening of other symptoms.

[68], [69], [70], [71], [72], [73]

Treatment of Comorbid Conditions

Depression

Many patients with schizophrenia, who are treated with typical neuroleptics, develop persistent symptoms of depression after exiting from an exacerbation. In these cases, you need to try to identify the patient's extrapyramidal side effects, assess the severity of negative symptoms and the effectiveness of treatment. If these causes of depressed mood are excluded, then diagnose "postpsychotic depression" and prescribe antidepressants. The drugs of choice in these cases are selective serotonin reuptake inhibitors (SSRIs), because, unlike tricyclic antidepressants, they are devoid of cholinolytic action, which can complicate patient recovery and care. In addition, with an overdose of SSRIs, the risk of death is lower than that of traditional antidepressants.

[74], [75], [76], [77], [78], [79], [80]

Addiction

Many people with long-term schizophrenia or schizophrenic-like psychosis develop addiction. These patients need to be recognized and treated in a timely manner. Many of them have an effective "12 steps" program. It is important to combine it with the use of antipsychotics, which help to maintain remission in patients. Since substance abuse increases the risk of developing tardive dyskinesia, these patients should prescribe atypical antipsychotics whenever possible.

[81], [82]

Psychogenic nolidypsy

Patients with chronic psychoses often suffer psychogenic polydipsia. This disorder appears to arise a second time, due to a malfunction in the brain of the mechanisms that suppress the feeling of thirst, and often does not lend itself to behavioral therapy. Psychogenic polydipsia is a potentially dangerous complication, as it can lead to impaired renal and cardiac function. In this case, the drug of choice are neuroleptics with minimal cholinolytic action, for example, risperidone or sertindole. In the absence of effect, the administration of clozapine, which can be useful in chronic psychogenic polydipsia, is possible, reducing, on the one hand, psychotic symptoms, and on the other hand, water consumption.

Non-compliance with patient prescription of a doctor (incompetence of patients)

Patients with long-term schizophrenia and schizophrenia-like psychosis find it difficult to follow the doctor's instructions. Since many of them are not able to adequately assess their condition, over time they often stop performing doctor appointments. The cause of non-compliance with prescriptions may be side effects and the absence of obvious treatment effect for the patient. If it is suspected that the patient has ceased to comply with the treatment regimen, it is necessary to subject it to a thorough examination to reveal even minimal manifestations of extrapyramidal disorders and akathisia. Often, these symptoms, which are not noticeable during examination, can very much disturb the patient. Their active therapy significantly increases compliance. To avoid the development of extrapyramidal disorders, a cautious correction of the dose of an antipsychotic may be required, which allows preserving the antipsychotic effect, but minimizing the side effects. Of the new generation drugs, the least risk of extrapyramidal complications, in addition to clozapine, is characteristic of sertindole and quetiapine. Olanzapine and risperidone can cause extrapyramidal disorders (although to a lesser extent than typical neuroleptics), which requires regular monitoring of the condition of patients. In particular, the likelihood of developing extrapyramidal complications when using risperidone becomes significant if its dose exceeds 8 mg / day.

If patients do not follow the recommendations, despite the absence of side effects, it is recommended to prescribe a drug-depot. Currently, two such drugs are used: haloperidol decanoate and fluphenazine decanoate. Haloperidol decanoate is administered at a dose of 25-100 mg intramuscularly once every 4 weeks. Although treatment sometimes starts with a higher dose, the tolerance of the drug is higher if its dose does not exceed 100 mg. Fluphenazine decanoate is prescribed in a dose of 25-50 mg intramuscularly once every 3-4 weeks. When using depot preparations, it is necessary to carefully examine the patient for extrapyramidal disorders and try to find the minimum effective dose (Schooler, 1996).

Persistent side effects

If the patient develops persistent bradykinesia or muscle rigidity, the dose of neuroleptic seems to be too high and needs to be reduced. If these symptoms persist after a dose reduction, the drug taken by the patient should be replaced with a neuroleptic of another class. If the patient is treated with a typical neuroleptic, they recommend switching to one of the atypical drugs. Bradykinesia and muscle rigidity can regress within a few months after the withdrawal of a typical neuroleptic, since the drug continues to slowly release from the "depot". Therefore, it is important to explain to the patient that after switching to a new drug, improvements can only be expected after a few weeks.

Similarly, with persistent akathisia, you should try to reduce the dose of the neuroleptic taken, but before - to find out if it does not exceed the minimum effective dose. If akathisia persists, the addition of propranolol or another beta-blocker may help. Sometimes it makes sense to switch to an antipsychotic drug of another class, including from one atypical neuroleptic to another. If and so it is not possible to correct akathisia, then it is advisable to administer clozapine.

Patients taking antipsychotics often experience problems in the sexual sphere, for example, they have lack of lubrication or impotence. Women may experience amenorrhea or dysmenorrhea; in men, as well as in women, galactorrhea, tenderness and swelling of the mammary glands are possible. Reduction of erection and disruption of lubrication, painful sexual intercourse can be explained by taking drugs with severe anticholinergic activity - these complications can be managed by lowering the dose or prescribing a drug with minimal cholinolytic activity. Drugs with severe adrenoblocking properties can also cause disturbances in the genital area. So, it was reported about the violation of ejaculation on the background of treatment with thioridazine; probably the same can be caused by other neuroleptics. In such cases, a reduction in the dose of the drug is also shown, and if this measure is ineffective, the drug is changed. Swelling and tenderness of the mammary glands, menstrual irregularities may be associated with an increase in the level of prolactin, the cause of which is the reception of a neuroleptic, effectively blocking dopamine receptors. Similar complications are observed when using typical antipsychotics, especially high-potential drugs, and when taking risperidone. Although in this case, a reduction in the dose of the drug may help, it often turns out that it is necessary to switch to a different class of drug.