Antipsychotics, or antipsychotics

Antipsychotics (neuroleptics) - a class of psychotropic drugs, mainly used to treat schizophrenia. Currently, it is common to distinguish two groups (or categories) of drugs: typical and atypical antipsychotics. Below are the data on the pharmacological properties, indications for the appointment and side effects of therapy for each of these groups of drugs.

[1], [2]

Indications for the appointment of typical antipsychotics

Currently, among the main indications for the appointment of traditional neuroleptics according to the recommendations given by authoritative researchers in the field of psychopharmacotherapy, include the following.

• Stimulation of psychomotor agitation and behavioral disorders, which are caused by pronounced psychotic symptoms. In these cases, the use of oral or parenteral forms of drugs with antipsychotic effect as a global (chlorpromazine, levomepromazine, thioproperazine, zuclopentixol) and selective - in the form of an effect on hallucinatory-paranoid disorders (haloperidol, trifluoperazine) is indicated.
• Antiretroviral (preventive) therapy. To this end, prescribe the deposited forms of drugs, especially in patients with poor medication compliance (haloperidol-decanoate, prolonged form of flupentixol), or small or medium doses of drugs to obtain a disinhibitory (anti- negative) effect, among those whose high doses are used for cupping acute psychotic disorders (flupenthixol, zuclopentixol). In this type of therapy, the appointment of so-called small antipsychotics (thioridazine, chloroprotoxen, sulpiride), whose psychotropic activity consists of exposure to depressive pole manifestations and dissomnic disorders, is also recommended.
• Overcoming therapeutic resistance to atypical antipsychotics when managing acute psychotic conditions. To this end, parenteral forms of traditional antipsychotics with a global (chlorpromazine, levomepromazine, etc.) and selective (haloperidol) antipsychotic action are usually used.

These drugs cause various side effects, the nature of which depends on the characteristics of the pharmacological profile of each drug. Antipsychotics with more pronounced anticholinergic effect more often cause disturbances in accommodation, constipation, dry mouth. Retention of urine. The sedative effect is more characteristic of antipsychotics with a pronounced antihistamine action, and orthostatic hypotension - means blocking a1-adrenergic receptors. Blockade with typical antipsychotics of cholinergic, nordrenergic and dopaminergic transmission can lead to a number of disorders in the genital area, such as amenorrhea or dysmenorrhea, anorgasmia, galactorrhea, swelling and tenderness of the mammary glands, a decrease in potency. Side effects in the genital area are mainly associated with the cholino- and adrenoblocking properties of these drugs, and in addition - with an increase in the secretion of prolactin due to blockade of dopamine metabolism. The most serious side effects of typical neuroleptics are violations of the motor function. They are the most common reason for patients to refuse medication. The three main side effects of therapy associated with the influence on the motor sphere are early extrapyramidal syndromes, tardive dyskinesia and NSA.

Extrapyramidal syndromes are associated, it is believed, with the blockade of D2 receptors in the basal ganglia. They include dystonia, neuroleptic parkinsonism and akathisia. Manifestations of an acute dystonic reaction (early dyskinesia) are suddenly evolving hyperkinesis, oculogic crises, contractions of the muscles of the face and trunk, opisthotonus. These disorders are dose-dependent and often occur after 2-5 days of therapy with high-grade neuroleptics, such as haloperidol and fluphenazine. To stop early dyskinesia, reduce the dose of neuroleptic and prescribe anticholinergic drugs (biperiden, triexyphenidyl). Late dyskinesia usually involves the muscles of the neck and, in contrast to the acute dystonic reaction, is less amenable to treatment with anticholinergics. For neuroleptic parkinsonism characterized by a decrease in the ability to spontaneous motor skills, hypo- and amy- mia, restless tremor and rigidity. These symptoms are important to distinguish from outwardly similar negative disorders in schizophrenia, represented by emotional alienation, blunting of affect and anergy. To correct these side effects shows the use of anticholinergics, a decrease in the dose of neuroleptic or its replacement by an atypical antipsychotic. Akathisia is manifested by internal anxiety, the inability to stay in one place for a long time and the need to constantly move your hands or feet. For its relief, use anticholinergics, as well as central beta-blockers (propranolol).

Late dyskinesia is manifested involuntary movements of any muscle group, more often muscles of the tongue and mouth. Clinically, a number of its forms are distinguished: dyskinesia of the muscles of the cheeks, tongue, mouth (periodic contractions of the masticatory muscles, creating impressions of the grimacing person, the tongue may involuntarily protrude from the patient's mouth); tardive dystonia and tardive akathisia; (the patient performs choreoathetoid movements of the head, trunk, upper and lower limbs). This form of disorders is mainly registered with long-term treatment with traditional antipsychotics and is detected in approximately 15-20% of patients who took them as maintenance therapy. Probably, in some patients the risk of developing symptoms of dyskinesia is increased, since some of them were observed in the clinic of schizophrenia even before the "neuroleptic era". In addition, tardive dyskinesia is described in elderly women and patients with affective disorders. It is suggested that tardive dyskinesia is associated with an increase in the number of dopamine receptors in the striatum, although GABA-ergic and other neurotransmitter systems are also likely to be involved in its pathogenesis. Effective universal treatment of such side effects does not exist. It is suggested that the administration of small doses of highly potent antipsychotic antipsychotics possessing dopamine-blocking action or vitamin E may have a moderate beneficial effect in these disorders. The most effective measure for tardive dyskinesia is a reduction in the dose of a typical neuroleptic or its replacement by an atypical antipsychotic.

Malignant neuroleptic syndrome, according to modern data, is observed in approximately 0.5% of cases of psychopharmacotherapy. Probably, the rare frequency of occurrence of such a life-threatening complication at the present time can be explained by the widespread introduction of atypical antipsychotics into practice, since the risk of NSA in treatment with these drugs is negligible. It is generally believed that the main reason for the development of the NSA is the excessive blockade of the dopaminergic system in the treatment with neuroleptics, especially after increasing the dose of a high-grade antipsychotics. The main symptoms of the NSA are hyperthermia, an increase in the tone of the skeletal muscles and tendon reflexes, a violation of consciousness with the transition to coma. The blood test reveals leukocytosis, an increase in the rate of erythrocyte sedimentation, the activity of hepatic transaminases; in the analysis of urine, the presence of albuminuria is noted. The violations of water and electrolyte balance quickly occur, which creates the prerequisites for the formation of edema of the brain. ZNS is an acute condition requiring urgent hospitalization of the patient for intensive infusion therapy. The treatment of NSA is most important hydration and symptomatic therapy. In this situation, any prescribed antipsychotics require immediate withdrawal. In some cases, dopamine receptor agonists (eg, bromocriptine) or muscle relaxants have a positive effect, although their effectiveness has not been studied. After eliminating the NSA, you should not resume taking an antipsychotic for at least two weeks. In the future, it is possible to prescribe a low-potential antipsychotic, preferably a new generation drug. The dose of the newly prescribed remedy should be increased very carefully, monitoring the state of vital functions and laboratory data (blood tests, urine tests).

Typical neuroleptics relatively rarely cause dangerous fatal complications. Manifestations of overdose are mainly associated with the individual profile of anti-adrenergic and anticholinergic action of the drug. Since these agents have a strong antiemetic effect, gastric lavage is indicated to eliminate them from the body, and not the administration of emetics. Arterial hypotension, as a rule, is a consequence of blockade of adrenoreceptors, and it should be corrected by the administration of dopamine and norepinephrine. If the heart rate is disturbed, the use of lidocaine is indicated.

The mechanism of action and pharmacological effects of typical antipsychotics

With the development of psychopharmacology, various variants of the influence of antipsychotics on neuroreceptors were proposed. The main one is the hypothesis about their effect on dopamine neurostructures (primarily D2 receptors), based on data on the disturbances in psychoses of normal dopamine metabolism in the structures of the brain. Dopamine D2 receptors are located in the basal ganglia, the adjacent nucleus and the cortex of the frontal lobes, they play a leading role in regulating the flow of information between the cortex and the thalamus.

The figure shows refined views on dopamine transmission in the cortical and subcortical areas of the brain and the role of these disorders in the development of symptoms of schizophrenia (adapted from the monograph Jones RV, Buckley PF, 2006).

Part "A" reflects the classic, early dopamine theory, the postulating dopamine excess in the subcortical areas and hyperstimulation of D2 receptors, which leads to productive symptoms. Part "B" demonstrates the subsequent modernization of the theory in the early 90's. Last century. Data obtained by this time revealed that the deficiency of dopamine in the receptors D; together with insufficient stimulation of these receptors of the prefrontal cortex leads to the appearance of negative symptoms and cognitive deficits. Therefore, according to modern understanding, both types of violations of dopaminergic transmission-an overabundance of subcortical dopamine and its deficiency in the prefrontal cortex-are the cumulative result of the disruption of synaptic transmission in the prefrontal region and are associated with the hypofunction of N-methyl-N-aspartate. In addition to the initially allocated dopamine, other neurotransmitters that participated in the pathogenesis of schizophrenia, such as serotonin, gammaaminobutyric acid, glutamate, norepinephrine, acetylcholine and various neuropeptides, were later identified. Although the role of these mediators is not fully understood, nevertheless, as knowledge develops, it becomes clear that the manifestation of numerous neurochemical changes in the body. Therefore, the clinical effect of the antipsychotic drug is the summation of the effects on various receptor formations and leads to the elimination of disturbance of homeostasis.

In recent years, in connection with the emergence of new research methods since the binding of radioisotope ligands and scanning PET, significant progress has occurred in the field of elucidating the subtle biochemical mechanism of action of neuroleptics. In particular, the comparative strength and tropicity of drugs for binding to individual neuroreceptors in various regions and structures of the brain is determined. The direct dependence of the antipsychotic effect of the drug on the strength of its blocking effect on various dopaminergic receptors is shown. Recently, four types of these receptors are distinguished:

• D1 are located mainly in the zone of black matter and the striatum (the so-called nigrostrial region), as well as the prefrontal area;
• D2 - in nigrostrial, mesolimbic areas and anterior pituitary gland (prolactin secretion);
• D3 (presynaptic) - in various structures of the brain, control dopaminergic activity according to the law of negative feedback;
• D4 (presynaptic) - mainly in the nigrostrial and mesolimbic regions.

At the same time, the fact that D2 receptor blockade is the cause of the development of antipsychotic, secondary sedative effects, as well as extrapyramidal side effects can now be considered proven. Other clinical manifestations of blockade of this type of receptors are the analgesic and antiemetic effect of neuroleptics (reduction of nausea, vomiting as a result of inhibition of the emetic center), as well as a decrease in the content of growth hormone and an increase in the production of prolactin (neuroendocrine side effects, including ha lactorrhea and menstrual irregularities). Prolonged blockade of nigrostrial D2-receptors leads to the appearance of their hypersensitivity, responsible for the development of late dyskinesias and "psychosis of hypersensitivity." The likely clinical manifestations of the blockade of presynaptic D3- and D4-receptors are mainly associated with the stimulating effect of neuroleptics. Due to the partial blockade of these receptors in the nigrostrial and mesolimbocortical regions, activating and incisional (powerful, highly active) neuroleptics in small doses can stimulate, and in high doses, inhibit dopaminergic transmission.

In recent years, interest in the function of serotonergic brain systems, including serotonin receptors, has increased sharply. The fact is that in different parts of the brain the serotonergic system has a modulating effect on the dopaminergic structures. In particular, in the mesocortical region, serotonin inhibits the release of dopamine, respectively, the blockade of postsynaptic 5-HT receptors leads to an increase in dopamine levels. As is known, the development of negative symptoms in schizophrenia is associated with hypofunction of dopamine neurons in the prefrontal structures of the cerebral cortex. At present, about 15 types of central 5-HT receptors are known. It has been experimentally found that neuroleptics bind mainly to the 5-HT-receptors of the first three types.

At 5-HT1a-receptors, these drugs have mainly a stimulating (agonistic) effect. Probable clinical consequences; intensification of antipsychotic activity, decrease in the severity of cognitive disorders, correction of negative symptoms, antidepressant effect and decrease in the number of extrapyramidal side effects.

Significant importance is the effect of neuroleptics on 5-HT2-receptors, especially on the 5-HT2a subtypes. They are found mainly in the cerebral cortex and their sensitivity in patients with schizophrenia is increased. With the blockade of 5-HT2a receptors, the ability of neuroleptics of the new generation to reduce the severity of negative symptoms, improve cognitive function, regulate sleep by increasing the overall duration of slow wave (D-wave) sleep stages, reduce aggression and weaken the depressive symptoms and migraine- brain disorders) headaches. On the other hand, with blockade of 5-HT2a receptors, there may be an increase in hypotensive effects and an ejaculation disorder in men.

It is believed that the effect of neuroleptics on 5-HT2c receptors causes a sedative (anxiolytic) effect, increased appetite (accompanied by an increase in body weight), and a decrease in the production of prolactin.

5-HT3 receptors are found predominantly in the limbic region, and their blockade primarily develops an antiemetic effect, and also enhances the antipsychotic and anxiolytic effect.

The appearance of parkinson-like symptoms also depends on the blocking effect of the drug on muscarinic cholinergic receptors. Holinolytic and dopamine-blocking actions are to a certain extent in reciprocal relationships. It is known, for example, that in the nigrostrial region, D2 receptors inhibit the release of acetylcholine. With blockade of more than 75% of D2 receptors in the nigrostrious region, the balance is disrupted in favor of the cholinergic system. This is the reason for the corrective effect on neuroleptic extrapyramidal side effects of cholinolytic drugs (correctors). Chlorprotixen, clozapine and olanzapine have a high tropism for muscarinic receptors and practically do not cause extrapyramidal side effects, since they simultaneously block choline and dopaminergic receptors. Haloperidol and phenothiazine derivatives of the piperazine series exert a pronounced effect on dopamine receptors, but very weakly affect choline. This is due to their ability to cause pronounced extrapyramidal side effects, which decrease with the use of very high doses, when the cholinolytic effect becomes palpable. In addition to reducing the dopamine-blocking effect on the D2 receptors of the nigrostrious region and leveling the extrapyramidal side effects, a strong cholinergic effect can lead to a deterioration in cognitive functions, including mastic disorders, as well as peripheral side effects (mucosal dryness, visual accidence, constipation, urinary retention, confusion, etc.). A fairly strong blocking effect of neuroleptics is on the histamine type I receptors, which is associated primarily with the severity of the sedative effect, as well as an increase in body weight due to increased appetite. Antiallergic and antipruritic action of neuroleptics is also associated with their antihistamine properties.

In addition to dopamine-blocking, antiserotonergic, anticholinergic and anticholinergic effects, most antipsychotics possess adrenolytic properties, i.e. Block both the central and peripheral a1-adrenergic receptors. Such adrenoblockers, as chlorpromazine and chlorprotixen, have a pronounced sedative effect. In addition, the blocking effect of these drugs is the cause of neurovegetative side effects (arterial hypotension, tachycardia, etc.), as well as strengthening the antihypertensive effect of adrenoblockers.

In the works of a large number of authors, data on the binding strength (affinity) of individual neuroleptics with various types of neuroreceptors are given. 

According to the neurochemical profile, typical and atypical antipsychotics among the ones used primarily in clinical practice can be conditionally divided into six groups.

The first group consists of selective blockers of D2- and D4-receptors (sulpiride, amisudppride, haloperidol, etc.) from the groups of benzamide and butyrophenone derivatives. In small doses, mainly due to the blockade of presynaptic D4 receptors, they activate dopaminergic transmission of nerve impulses and have a stimulating (disinfecting) effect, in large doses block D2 receptors in all areas of the brain, which clinically manifests a pronounced antipsychotic effect, as well as extrapyramidal and endocrine (in view of prolactinemia) by side disorders.

The second group includes highly active blockers of D2 receptors, as well as drugs that weakly or moderately block 5-HT2a- and 5-HT1a receptors (flupentixol, fluphenazine, zuclopentixol, etc.), i.e. Mainly piperazine derivatives of phenothiazine or thioxanthenes close to them in the stereochemical structure. Like preparations of the first group, these antipsychotics have, first of all, a pronounced antipsychotic (incisive) effect, and also cause extrapyramidal peen effects and prolactinemia. In small doses, they have a moderately activating (psychostimulating) effect.

The third group is made up; multivalent sedative neuroleptics, undifferentiated most of the neuroreceptors. These drugs have a clearly expressed blocking effect on dopamine receptors, and also cause strong adrenolitic and cholinolytic effects. This includes most sedative neuroleptics, especially aliphatic and piperidine derivatives of phenothiazine, as well as thioxanthenes (chlorpromazine, levomepromazine, chloroproticsen, etc.), close to them in terms of the stereochemical structure. In the spectrum of psychotropic activity of these drugs, predominantly, a pronounced primary sedative effect, which develops independently of the applied dose, and a moderate antipsychotic effect predominate. In addition, drugs of this group due to severe cholinolytic effects cause mild or moderate extrapyramidal and neuroendocrine side effects, but often lead to the development of orthostatic hypotension and other vegetative reactions due to the expressed blockade of a1-adrenergic receptors.

The fourth group includes neuroleptics, in a balanced way, i.e., to the same extent, blocking D2- and 5-HT2a receptors (the latter to a somewhat greater extent) and to a moderate extent - a1-adrenergic receptors. This group includes members of a new generation of atypical antipsychotics (risperidone, ziprasidone, sertindole) having a different chemical structure. The neurochemical mechanism of action determines their selective influence primarily on the mesolimbic and mesocortical regions of the brain. In addition to the distinctive antipsychotic effect, the absence or weak severity of extrapyramidal side effects (with therapeutic doses), mild or moderate prolactinemia and moderate adrenolithic properties (antihypertensive reactions), this group of neuroleptics is able to correct negative symptoms by mediating stimulation of dopaminergic transmission in the cerebral cortex.

The fifth group consists of polyvalent atypical antipsychotics of tricyclic dibenzodiazepine or a structure close to it (clozapine, olanzapine and quetiapine). Just like the drugs of the third group, they undifferentially block most of the neuroreceptors. However, 5-HT2a receptors block more strongly than D2 and D4 receptors, especially located in the nigrostrious region. This determines the actual absence or weak extrapyramidal effect and the absence of neuroendocrine side effects associated with increased production of prolactin with a distinct antipsychotic effect and the ability to reduce the severity of negative symptoms. In addition, all drugs of this group have pronounced adrenolitic and antihistamine properties, which determines sedative and hypotensive effects. Clozapine and olanzapine have a fairly pronounced blocking effect also on muscarinic receptors and lead to the development of cholinolytic side effects.

Thus, the ability to block postsynaptic dopaminergic receptors with compensatory enhancement of synthesis and metabolism of dopamine is the only common biochemical property for all neuroleptics examined in these groups.

The sixth group includes so far the only atypical antipsychotic aripiprazole, which comparatively recently appeared on the domestic psychopharmacological market. This drug is a partial agonist of D2-dopamine receptors, and acts as a functional antagonist in the hyperdophaminergic state and as a functional agonist in the hypodofaminergic profile. This unique receptor profile of aripiprazole makes it possible to reduce the risk of extrapyramidal disorders and hyperprolactinemia when it is used. In addition, aripiprazole acts as a partial agonist of 5-HT1a receptors and at the same time it is an antagonist of 5-HT2a receptors. It is suggested that such interaction with receptors leads to a generally balanced functioning of the serotonin and dopamine systems, therefore the mechanism of action of aripiprazole can be designated as stabilizing the dopamine-serotonin system.

Thus, the current level of knowledge about the neurochemical mechanisms of action of neuroleptics allows us to propose a new pathogenetically more substantiated pharmacodynamic classification of this group of psychotropic drugs. The use of this classification makes it possible to predict to a large extent the spectrum of psychotropic activity, tolerability and probable drug interactions of a given drug. In other words, the characteristics of the neurochemical activity of the preparation largely determine the characteristics of its clinical activity, which should guide the selection of an antipsychotic drug for a particular patient.

The effectiveness of the global antipsychotic effect of any neuroleptic is evaluated using the so-called chlorpromazine equivalent, which is taken as 1. For example, the chlorpromazine equivalent of haloperidol = 50. This means that the antipsychotic efficacy of 1 mg of haloperidol is comparable to 50 mg of chlorpromazine. Based on this indicator, a classification has been developed that provides for the isolation of antipsychotics having high (chlorpromazine equivalent> 10.0), medium (chlorpromazine equivalent = 1.0-10.0) and low (chlorpromazine equivalent = 1.0) antipsychotic activity, called patentability. Typical antipsychotics (antipsychotics of the first generation) for almost half a century were widely used in clinical psychopharmacotherapy. The spectrum of their therapeutic activity includes:

• global antipsychotic action in the form of ability to differentially and differentially reduce the various manifestations of psychosis:
• primary sedative (inhibitory) action - the ability of drugs to quickly stop psychomotor agitation;
• selective, selective antipsychotic effect, manifested in the ability to affect individual symptoms: delirium, hallucinations, disinhibition of drives, etc .;
• activating (disinhibiting, disinhibiting, anti-auretic) neurotropic action, manifested by the development of extrapyramidal symptoms;
• somatotropic action in the form of development of neuroendocrine and vegetative side effects;
• depressor effect, expressed in the ability of some antipsychotics to cause depressive symptoms.

The effectiveness of first-generation antipsychotics in the treatment of not only psychotic disorders, but also violations in borderline psychiatry, has been repeatedly proven and undeniable. Therefore, despite the high frequency of side effects of therapy when they are prescribed, they continue to be used in medical practice.

Atypical antipsychotics

Modern guidelines contain data on the benefits of using the second generation of antipsychotics in pharmacotherapy. The term "atypical" (a synonym - antipsychotics of the second generation) is conditional and use it mainly for the convenience of designating a new generation. Preparations of this group in comparison with traditional neuroleptics are more effective in correcting negative, affective and cognitive disorders, which is combined with better tolerability and a lower risk of extrapyramidal symptoms. Differences in the nature of the therapeutic effect of this or that remedy from a number of atypical antipsychotics explain, as in the group of typical neuroleptics, its individual profile of pharmacological effects.

To clarify the possibilities of psychopharmacotherapy atypical antipsychotics, it is advisable to dwell on the preparations of this group registered in Russia.

[29], [30], [31], [32], [33], [34],

Clozapine (dibenzodiazepine)

The ancestor of a group of atypical antipsychotics. The mechanism of action of clozapine is characterized by a slight blockade of D2 receptors with a simultaneous high antagonism to 5-HT2a receptors, a1, a2-adrenergic and H1-histamine receptors. It has established itself as an effective antipsychotic in cases of resistance to other antipsychotics (a drug of the reserve group), and is also indicated for the treatment of chronic mania, psychotic agitation, aggression. In domestic practice, clozapine is often prescribed to achieve sedation and as a hypnotic in psychotic patients. It should be recognized that such a use of clozapine does not correspond to its main profile of indications for use in therapy. Probably, the attitude to this antipsychotic as a preparation of secondary importance should be reconsidered, because today it is the only remedy with proven efficacy in resistant patients.

Clozapine, in contrast to typical neuroleptics, does not cause serious ecstapiramid disorders due to the low affinity noted above for 02-receptors. It also turned out that it can be used to treat late dystonia and severe akathisia. In view of the small risk of developing the ZNS, clozapine can be considered as a drug of choice in patients who previously suffered this complication.

Nevertheless, with clozapine therapy, a number of serious side effects may develop. The most dangerous of them (even with the appointment of small doses) is agranulocytosis, which occurs in 0.5-1.0% of patients. Among other important side effects, possible with the use of the drug, it should be noted drowsiness, hypersalivation and weight gain, which is often increased by the time of the appointment of clozapine under the influence of previous antipsychotic therapy. It should also pay attention to the possibility of developing with its intake of tachycardia, arterial hypotension and epileptic seizures. The likelihood of 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 for the further administration of the drug, but requires a half dose reduction and the administration of anticonvulsants, such as valproic acid. Prevention of side effects of clozapine treatment includes careful monitoring of the white blood picture, as well as ECG and endocrine parameters.

With an overdose of clozapine, depression is possible up to the development of coma, as well as symptoms associated with the holinolitic effect (tachycardia, delirium), epileptic seizures, respiratory depression, extrapyramidal syndromes. Lethal outcome may occur when taking a dose exceeding 2500 mg of the drug.

[35], [36], [37], [38], [39], [40], [41], [42],

Risperidone

A benzisoxazole derivative with a high affinity for serotonin and dopamine Dj receptors with a predominant effect on the serotonin system. The drug has extensive indications for use, including relief exacerbation, anti-relapse therapy, therapy of the first psychotic episode, correction of negative symptoms of schizophrenia. The ability of the drug to improve the cognitive functioning of patients with schizophrenia is noted. Preliminary data have been obtained that risperidone also reduces comorbid affective symptoms in patients with schizophrenia and may be the drug of choice in the therapy of bipolar affective disorders.

Side effects of risperidone therapy, especially extrapyramidal disorders, are dose-dependent and occur more often at a dose exceeding 6 mg / day. Other side effects include nausea, vomiting, anxiety, drowsiness, increased serum prolactin levels. Long-term use of risperidone may lead to an increase in body weight and the development of type 2 diabetes, but less likely than clozapine, olanzapine.

In case of an overdose, somnolence, epileptic seizures, prolongation of the QT interval and expansion of the QRS complex, arterial hypotension are possible. Cases of lethal outcome in case of risperidone overdose are described.

The undoubted advantage of the drug - the presence of liquid and rapidly dissolving (sublingual) forms, the use of which accelerates the receipt of the drug in the patient's body and facilitates control over its intake. There is also a prolonged form of the drug - a powder for the preparation of a suspension for intramuscular injection (constapperpiperidone in microspheres). It is recommended for supportive treatment of schizophrenic patients, especially for patients with poor compliance. It is necessary to take into account the fact that it takes about three weeks to get into the bloodstream, so when starting therapy with constipersperidone, the patient should additionally take the oral form of risperidone for at least 3 weeks after the first injection.

Olanzapine

By pharmacological action is close to clozapine, since it has a pleomorphic receptor profile with significant affinity for serotonin, muscarinic, a1-adrenergic, histamine receptors. The therapeutic activity of olanzapine has similarities to the efficacy of clozapine and risperidone in affecting the positive, negative and depressive symptoms of schizophrenia. At the same time, data were obtained on the greater efficacy of olanzapine compared to other atypical antipsychotics in patients with the first psychotic episode and in the correction of cognitive performance. It should be borne in mind that at the beginning of therapy with the use of a tablet form of the drug, a rapid appearance of a disinhibitory effect with an increase in psychomotor agitation and anxiety is possible. Therefore, in the treatment of seizures accompanied by severe psychomotor agitation, the use of the injection form of the drug is indicated.

Olanzapine rarely causes extrapyramidal disorders or tardive dyskinesia, and the most common side effects when used are metabolic disorders and weight gain. It has been established that in patients receiving olanzapine, the levels of cholesterol and plasma lipids often increase and a predisposition to type 2 diabetes appears, but similar effects were equally common in patients receiving both olanzapine and clozapine. At the same time, data have been obtained that the increase in body weight correlates with a positive response to olanzapine (that is, it serves as an important prognostic indicator of therapy), but grows into obesity - only in 20-30% of patients gaining excess body weight in the process treatment.

In case of an overdose, a sedative effect, toxic cholinolytic action, epileptic seizures, arterial hypotension are possible. To date, there is no convincing evidence to assess the risk of death in overdose of the drug.

Quetiapine

Refer to dibenzothiazepine compounds. Its receptor profile is similar in many ways to that of clozapine. The level of binding of quetiapine to D2 receptors is low (less than 50%) and short-term even when high doses are used. The drug is effective for the treatment of positive, negative and general symptoms of schizophrenia. There are data on the successful use of it in both cases of high resistance to therapy, and to improve the indicators of cognitive functioning of patients, which gives the right to recommend it as an antipsychotic of the first line for maintenance therapy of schizophrenia. Finally, quetiapine has a moderately antidepressant, activating effect. Therefore, it is indicated in the therapy of depressive-delusional attacks and disorders of the senesto-hypochondriacal circle.

The established high thymotropic activity of quetiapine explains the fact that it is registered as a remedy for relieving and secondary prevention of depressive disorders. For the treatment of manic episodes within the framework of bipolar disorders of type I and II, quetiapine is used as an additional agent. The lack of injection forms somewhat limits its use in patients with arousal and aggressive behavior.

Quetiapine has a fairly good tolerance, it practically does not cause extrapyramidal syndromes, except when the maximum doses are used. Quetiapine does not cause hyperprolactinaemia, less often than olanzapine and clozapine, leads to an increase in body weight and impaired glucose tolerance.

Ziprasidone

Has a unique profile of receptor activity. Being a potent antagonist of 5HT2a receptors and D2 receptors, it is also an active inhibitor of the reuptake of serotonin and norepinephrine. Clinical studies have demonstrated a significant superiority of ziprasidone in its effect on psychotic symptoms and manifestations of aggression compared with haloperidol. Also, data on the positive effect of ziprasidone on the cognitive functions of schizophrenic patients, as well as on comorbid affective symptoms, indicators of social functioning were obtained. Ziprasidone is usually well tolerated and extremely rarely causes extrapyramidal syndromes, weight gain and metabolic disturbances. Often there is an extension of the QT interval above 460 ms, so patients receiving this drug, it is advisable to conduct an ECG study before the appointment of the drug, and monitoring monitoring during treatment. Special attention should be paid to concomitant therapy (antiarrhythmic drugs), which can aggravate the prolongation of the QT interval and lead to cardiac arrhythmia, ventricular fibrillation.

Sertindole

Refer to derivatives of phenylindole. It has a high functional antagonism with respect to D2-, serotonin (especially 5-HT2a receptors) and a1-adrenergic receptors. According to electroneurochemical studies, sertindole selectively inhibits dopamine receptors in the ventral segmental region. This selectivity, in all likelihood, provides a low risk of extrapyramidal syndromes and hyperprolactinaemia when the drug is used. The results of comparative studies have shown that sertindole is comparable with haloperidol in terms of antipsychotic activity. The drug has a pronounced disinhibitory effect in patients with negative and depressive symptoms, which exceeds the similar effect of rispolept. There are also data confirming the effectiveness of sertindole for correction of cognitive impairment in patients with schizophrenia. Sertindole, as a rule, is well tolerated by patients, rarely causes sedation and is therefore recommended as a substitute drug for the occurrence of side effects during therapy with other modern antipsychotics.

Of the serious side effects noted the ability of the drug to extend the interval of Q-T, which can lead to cardiac arrhythmia. When analyzing post-marketing research, it became apparent that the cardiological profile of sertindole does not differ from that of other antipsychotics of the new generation.

Aripiprazole

Has comparable with other atypical agents antipsychotic activity, but it has a greater impact on the parameters of cognitive functioning of schizophrenic patients. The unique pharmacological action of the drug, a partial agonist of D2 receptors, noted above, makes it possible to reduce the risk of extrapyramidal syndromes and hyperprolactinemia when it is used.

[43], [44], [45], [46], [47], [48]

Amisulpride

They refer to the class of substituted benzamides. The drug selectively binds to subtypes of D2- and D3-dopaminergic receptors, does not have affinity for the subtypes D1-, D4- and D5-, as well as for serotonin, H1-histamine, a1-adrenergic and cholinergic receptors. When used in high doses, it blocks postsynaptic D2 receptors. At low doses, its disinhibitory effect is manifested due to blockade of presynaptic D2-, D3-receptors, and therefore its use is also effective in the treatment of negative symptoms, although it is not a combined antagonist of D2 receptors and serotonin receptors. The results of a number of studies indicate a pronounced antipsychotic activity of the drug when using high doses, which is superior to traditional drugs.

[49], [50], [51], [52], [53], [54], [55], [56],

Side effects of antipsychotic therapy

The table shows the main side effects of therapy with atypical antipsychotics.

A drug	Extra-pyramidal syndromes	Conductivity disorder on the ECG	Metabolic disorders (weight gain, increase in glucose, cholesterol, triglycerides in the blood)
Clozapine	.	++		++	++ -
Risperidone	++	+/-	++	+/-
Olanzapine	+	+/-	+++	++	+++
Quetiapine		+/-	+	+/-	---
Ziprasidone	+	++	+/-	+/-	+/-
Sertindole		++	-	+/-	-
Ariliprazole	-	---	+/-	-	-
Amisulpride	++				+/-

Note. Severity of side effects: "+++" - high: "++" - medium; "+" - low; "+/-" - doubtful; "-" - absent.

Extrapyramidal syndromes

One of the main features of atypical antipsychotics, unlike traditional ones, is their low ability to cause extrapyramidal syndromes, which was a breakthrough in supporting pharmacotherapy of schizophrenia. However, as follows from the data of the table, when using certain drugs of this series (risperidone, amisulpride), such symptoms can arise, which requires special attention when they are assigned.

[3], [4], [5], [6], [7], [8], [9], [10],

ECG disorders

The possibility of developing cardiological side effects is a serious problem when using some modern antipsychotics in therapy. In these cases, it is an extension of the Q-T interval, which can lead to arrhythmia. Conduction disruption, especially the prolongation of the Q-T interval, is most often observed with clozapine, sertindole, ziprasidone. Concomitant pathology in the form of bradycardia, atrioventricular blockade, hypothyroidism may contribute to the occurrence of this complication in the treatment of the above drugs. Currently, ECG monitoring is recommended approximately every 3 months in patients receiving maintenance therapy with atypical antipsychotics.

[11], [12], [13], [14], [15]

Endocrine disorders

At present, the greatest concern is the ability of atypical antipsychotics to cause weight gain. The increase in body weight, glucose, triglycerides in the blood can lead to metabolic disorders and the development of type 2 diabetes. Especially careful and weekly monitoring of biochemical parameters during the therapy with clozapine and olanzapine is necessary. According to J. Geddes et al. (2000), R.V. Jones, PF Buckley (2006), it should be recognized that it is advisable to conduct a thorough examination of patients before prescribing an antipsychotic of modern generation, since metabolic disorders are more likely to occur in patients with hereditary predisposition, excessive body weight, lipid spectrum disorders and hyperglycemia before treatment. The monitoring algorithm proposed by P. V. Jones, PF Buckley (2006), includes several items.

• Collection of anamnesis and family factors regarding the risk of metabolic disorders.
• Registration of body mass index, ECG, blood pressure and pulse before treatment.
• Collection of laboratory data (glucose, lipid spectrum, cholesterol) before the start of therapy.
• Regular monitoring of body mass index, vital signs during treatment.
• Control of laboratory data during treatment.

The appearance of hyperprolactinaemia in antipsychotic therapy is due to the central blockade of dopamine receptors in the hypothalamus, which leads to the release of prolactin in the anterior lobe of the pituitary gland. The most common hyperprolactinemia occurs when treated with olanzapine, risperidone, and amisulpride.

[16], [17], [18], [19], [20]

Agranulocytosis

Another serious complication of antipsychotic therapy. It can be observed with clozapine and olanzapine. According to J. Geddes et al. (2000), he was diagnosed during the first 3 months in 1-2% of patients taking these drugs. In this regard, recommend a weekly blood test in patients taking these drugs during the first 18 weeks of therapy and monthly monitoring in the future. It was shown that when the dose of the above neuroleptics decreased, the clinical blood test again returned to normal. At the same time, it should be recognized that there is currently no clear strategy for patients who experience the side effects associated with a metabolic disorder. Most often replace one atypical antipsychotic on another. Another promising area should be the appointment of special corrective therapy, in particular the use of the drug bromocriptine for the correction of hyperprolactinemia. Ideal should be considered a situation in which a patient with such disorders is cured with periodic involvement of internists, in particular endocrinologists, cardiologists and other specialists.

In conclusion, it should be noted that, in accordance with the above algorithms for the appointment and monitoring of not only the mental, but also the physical state of patients, second-generation drugs are safer than typical neuroleptics.

Currently, a number of antipsychotics are being developed. Preparations of the next generation are likely to have a different mechanism of action (for example, to have GABA-ergic profile) and will be able to influence various manifestations of schizophrenia, including the actual deficiency disorders.

[21], [22], [23], [24], [25], [26], [27], [28],