Antidepressants

Antidepressants - a group of psychotropic drugs, including synthetic drugs of different chemical structure, and drugs that are of natural origin (for example, St. John's wort).

For almost half a century of clinical use of antidepressants for their systematization various methodological approaches were used.

[1], [2],

Pharmacodynamic classification

It is based on ideas about the effects that reflect the effect of antidepressants on various neurotransmitter systems. According to the main mechanism of action, drugs are divided into the following groups:

1. Inhibitors of presynaptic capture of neurotransmitters.
2. Blockers of pathways of metabolic destruction of neuroamines.
3. Activators of serotonin reuptake.
4. Antidepressants with a receptor mechanism of action.

This division is relatively arbitrary, since it reflects only the primary pharmacological action of the antidepressant. For practical work, an overall assessment of the pharmacological profile of the preparation is important, including both the primary point of its application and the nature of the effect on other receptors.

The following is a description of groups of antidepressants not only registered in the Russian Federation, but also those used in foreign clinics. The description of the latter is made in order to inform practicing doctors about the merits and demerits of a given drug from the modern arsenal of antidepressants.

Mixed classification of antidepressants

The classification was created in the middle of the last century and provided for the separation of drugs into two main groups: irreversible MAO and TA inhibitors. It was of definite clinical importance, because at that stage in the development of psychiatry, it was shown that severe endogenous depressions are better suited for therapy with thiazide diuretics, and with neurotic depressions, the administration of MAO inhibitors is more effective. Thus, it was simultaneously used two principles of drug separation, namely, by their chemical structure and the nature of the therapeutic effect. Currently, it has a greater historical significance, although it has already been initially identified, the basic principles for the subsequent differentiation of antidepressants.

Classification of antidepressants by chemical structure

In the clinical aspect, it is of little informative, since it does not give any idea of the efficacy or side effects of antidepressant therapy. However, it is of great importance for the synthesis of new agents taking into account their stereochemical characteristics. An example is the isolation of escitalopram, which, together with the R-enantiomer, enters the citalopram molecule. After elimination of R-citalopram, a more potent effect of the new antidepressant on serotonin reuptake was obtained, leading to greater clinical efficacy and better tolerability than the predecessor. The creation of this drug allowed researchers to talk about "allosteric modulation", which strengthens antidepressant action, with the allocation of a special class of antidepressants - allosteric inhibitors of serotonin reuptake.

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

Inhibitors of presynaptic engagement of neuromediators

Currently, these antidepressants are most widely used in practice. The first hypothesis, explaining the mechanism of antidepressant activity of imipramine as the ancestor of this group, distinguished its influence on adrenergic systems. It was further developed in J. Glowinski, J. Axelrod (1964), who showed that imprramin inhibits the reuptake of norepinephrine in the ends of the presynaptic nerve fibers, which leads to an increase in the amount of the mediator in the synaptic cleft. Later, it was found that imipramine inhibits not only the reuptake of norepinephrine, but also serotonin.

In the same years, the first attempts were made to discover the connection between the clinical effects and the pharmacological profile of the first antidepressants. It was suggested that the blockade of serotonin reuptake, accompanied by its accumulation, leads to an improvement in mood, and blockade of norepinephrine reuptake correlates with an increase in activity. However, based on the initial hypotheses, it was difficult to explain the fact that the pharmacological effect (increasing the level of neurotransmitters) of antidepressants appears almost immediately, and the therapeutic effect is manifested only after 2-3 weeks. Later it was found that the therapeutic effect of antidepressants is associated not so much with the phenomenon of inhibition of the reuptake of neurotransmitters, but rather with a change in the sensitivity of the synaptic receptors to them. This marked the beginning of the development of adaptive hypotheses of the therapeutic action of antidepressants. Studies have shown that the chronic use of most antidepressants causes a number of changes in postsynaptic membranes, such as a reduction in the density of serotonin 5-HT2 and a2-adrenergic receptors, an increase in the number of GABAergic receptors, etc. One of the new concepts suggests that depression is the result disruption of the work of neural networks, and the work of antidepressants is to improve information processes in damaged networks. At the heart of the damage to these networks is the violation of the processes of neuroplasticity. Thus, it turned out that prolonged use of antidepressants increases the development of new neurons in the hippocampus and other parts of the limbic system of the brain. These observations are especially important for understanding the cause of the peculiar action of antidepressants in their appointment, regardless of the type of drug: the cellular response is delayed in time, which explains the reason for the delayed response to antidepressant therapy.

After the discovery of imipramine, the synthesis of new drugs was on the way of creating drugs with a close chemical structure, which are still traditionally called tricyclic antidepressants.

In the English and Russian literature there are differences in terminology. Thus, in the domestic literature, the term "tricyclic antidepressants" (TA) means antidepressants of only a tricyclic structure, while in the English-language literature, the TA group includes preparations of both a tricyclic and a tetracyclic structure. This approach is artificial to a certain extent, since the preparations having a tri- and tetracyclic structure differ not only in chemical structure, but also in the mechanism of action. For example, the tetracyclic antidepressant mianserin has a unique mechanism of action, by which it increases the release of norepinephrine by blocking presynaptic a2-adrenergic receptors.

In the future, with the accumulation of experience in clinical use, the development of drugs took into account their selectivity, i.e. Ability to selectively influence certain receptors. Non-selective inhibitors of neurotransmitter reuptake.

Classical tricyclic antidepressants, depending on the number of methyl groups on the nitrogen side - the side chain, are divided into secondary and tertiary amines. Tertiary amines include amitriptyline, imipramine, and clomipramine; to secondary - nortriptyline, desipramine. It is believed that tertiary amines have a greater affinity for serotonin receptors, while secondary amines are associated with noradrenergic receptors. The greatest effect on the reuptake of serotonin from the group of classical TA is provided by clomipramine. All preparations related to tertiary amines have approximately the same effect on norepinephrine reuptake. Some authors consider it expedient to isolate TA with predominant serotonergic (C-TA), noradrenalinergic (H-TA) action. According to S.N. Mosolova (1995), the clinical significance of this division is doubtful, and this is due not only to the fact that noradrenergic and serotonergic systems are closely related, but also because most TAs do not have selectivity and block almost equally the presynaptic seizure of noradrenaline and serotonin. Confirmation of this and the fact that tertiary amines are metabolized in the body to secondary amines. The active metabolites of these drugs - desipramine, nortriptyline and desmethylclomipramine, affecting the noradrenaline transmission, - participate in the holistic antidepressant effect of the drug. Thus, most traditional TA are drugs that affect both the reuptake of serotonin and norepinephrine. All representatives of this group of antidepressants have very little effect on the re-uptake of dopamine. Simultaneously, they are compounds with a broad neurochemical profile and are capable of causing a variety of secondary pharmacodynamic effects. They can affect not only the capture of monoamines, but also the central and peripheral cholinoreceptors of the muscarinic type, a2-adrenergic receptors and histamine receptors, with which most side effects of therapy are associated.

The side effects of classical tricyclic antidepressants are diverse.

With peripheral holinoblokiruyuschim TA action associated with dry mouth, mydriasis, increased intraocular pressure, disruption of accommodation, tachycardia, constipation (up to paralytic ileus) and delayed urination.

In this regard, drugs are contraindicated in glaucoma, prostatic hyperplasia. Peripheral anticholinergic effects are dose-dependent and disappear after a decrease in the dose of the drug.

With the central anticholinergic effect of these antidepressants, the possible development of delirium and convulsive seizures is associated with their admission. These side effects also have a dose-dependent effect. In particular, the risk of developing delirium increases with a concentration of amitriptyline in the blood that exceeds 300 ng / ml and is more likely to occur when the concentration reaches 450 ng / ml with amitriptyline. Anticholinergic effects can also contribute to the development of tachycardia.

The sedative effect is associated with the blockade of these antidepressant histamine H1 receptors. It can be used to treat sleep disorders associated with depression, but daytime sleepiness often makes therapy difficult and causes patients to be negative about taking medication. Preparations with a sedative effect are advisable to appoint patients with severe anxiety at the first r | stages of therapy, but on later surplus sedation makes it difficult to adequately assess the patient's condition.

Classical TA have pronounced cardiotoxicity, which is manifested by impaired conduction in the atrioventricular node and ventricles of the heart (quinine-like action), arrhythmias, and a decrease in the contractile ability of the myocardium.

With long-term admission of classical TA, an increase in appetite may be possible, followed by an increase in body weight, which increases the already high risk of forming a metabolic syndrome in depression.

A serious reason why one should be very cautious when assigning classical TA is the frequency of completed suicides associated with an overdose of the drug. In the literature, there is a direct correlation between the administration of these remedies and the fatal outcome of suicidal attempts.

The side effects of therapy cause caution in the appointment of classical TA. According to the modern standards of therapy for depression developed by WHO experts, these drugs are not first-line drugs and their use is recommended only in a hospital setting for two reasons. First, because of the large number of different side effects. Secondly, with the appointment of classical TA, dose titration is necessary. Patients before the appointment of these funds should undergo a survey in order to exclude clinically significant somatic disorders. Considering the expressed cardiotoxic effect, ECG should be performed before prescribing this group. Patients with a QT interval greater than 450 ms represent a risk group for complications from the cardiovascular system, so the use of these agents is undesirable; the presence of glaucoma or adenoma of the prostate gland is also a contraindication for the appointment of classical TA.

SSRIs are a group of drugs that are heterogeneous in chemical structure (single-, double- and multicyclic compounds), but possess a common mechanism of action. Antidepressant activity of SSRIs has been demonstrated in a large number of controlled studies. SSRIs have found wide application not only in the treatment of depression, but also for the treatment of diseases of the depressive spectrum (obsessive-compulsive, anxiety and phobic disorders, social phobia, etc.). SSRIs in modern world clinical practice - first-line drugs for depression therapy. This group includes 6 antidepressants; fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram.

Fluoxetine from all SSRIs has the strongest inhibitory effect on 5-HT2c receptors. The inhibition of these receptors affects the activity of norepinephrine and dopamine systems. This influence determines the activating properties of the drug, which are more pronounced in it than in other SSRIs. Such an effect from the clinical point of view can be characterized as indeterminate. On the one hand, the effect of the drug on 5-HT2c receptors can cause insomnia, increased anxiety, the development of stimulation. On the other hand, this pharmacological action is desirable in patients with hypersomnia, inhibition and apatoanergic depression.

Sertraline, in contrast to other antidepressants of this group, has the ability to block the re-uptake of dopamine, but weaker than the inhibition of reuptake of serotonin. The effect on re-uptake of dopamine occurs when the drug is used in large doses. The result of affinity for dopamine receptors is its ability to cause extrapyramidal symptoms. Sertralin is effective in the treatment of melancholic, prolonged depressions, as well as psychotic depression.

Fluvoxamine has a unique clinical effect, which we explain by its secondary pharmacodynamic properties, namely the effect on D1 receptors, which are associated with stimulation of cognitive activity. Thus, fluvoxamine can be considered a drug of choice in the treatment of depression in elderly patients, accompanied by severe cognitive impairment. In addition, the presence of a positive effect on cognitive processes and memory makes it appropriate to use it in patients engaged in mental work.

Paroxetine is the most potent inhibitor of serotonin reuptake, in addition, it is stronger than other SSRIs, inhibiting the reuptake of norepinephrine. This effect in paroxetine is not as pronounced as in TA (amitriptyline). The drug, in comparison with other SSRIs, also has the greatest affinity for muscarinic receptors. Therefore, when using paroxetine, constipation, urinary retention, and a tendency to increase in body weight are more often recorded. In addition, he has a stronger sedative effect than others, which can be used to treat patients with severe anxiety.

Citalopram has the greatest affinity for histamine H1 receptors in comparison with other SSRIs. The affinity of the drug for H1 receptors, for example, is more than 100 times greater than that of fluvoxamine. This is associated with the ability of citalopram to increase cravings for carbohydrates and thus contribute to the development of obesity.

Escitalopram is the active S-enantiomer of citalopram. Escitalopram has a different mechanism of action than other serotonergic antidepressants: it interacts not only with the primary site of binding of the serotonin transport protein, but also with the secondary (allosteric) site, which leads to a faster, more powerful and persistent blockade of serotonin reuptake due to the modulating effect of allosteric binding. At the same time, escitalopram is characterized by a lower affinity for histamine H1 receptors than citalopram.

The side effects of SSRIs are related to the effect on the serotonin powertrain. Serotonin receptors are widely represented in the central and peripheral nervous system, as well as in organs and tissues (smooth muscles of the bronchi, gastrointestinal tract, vessel walls, etc.). The most frequent side effects are disorders from the gastrointestinal tract: nausea, less often vomiting, diarrhea (due to excessive stimulation of 5-HT3 receptors of serotonin 3 sub-type). These disorders are very often (in 25-40% of cases) occur in the early stages of therapy and are transient. To reduce the likelihood of their occurrence, it is recommended to start therapy with low daily doses of drugs with subsequent increase by 4-5 days of treatment.

Excitation of serotonin receptors can be accompanied by tremor, hyperreflexia, violation of coordination of movements, dysarthria, headache. Approximately 30% of patients on the background of SSRIs (especially paroxetine, sertraline) experience sexual dysfunction, manifested in weakening of erection, delayed ejaculation, partial or complete anorgasmia, which often leads to the refusal to continue therapy. These undesirable phenomena are also dose-dependent, and when they appear, a dose reduction is recommended.

The most dangerous complication of therapy with these antidepressants is "serotonin syndrome". According to S.N. Mosolova et al. (1995), the initial manifestations of serotonin syndrome mainly affect the gastrointestinal and nervous systems of the body. Initially, there is turbulence, colic in the abdomen, flatulence, loose stools, nausea, less often vomiting and other dyspepsia. Neurological symptoms include extrapyramidal symptoms (tremor, dysarthria, restlessness, muscle hypertonia), hyperreflexia and myoclonic twitching, which usually begin with the feet and spread throughout the body. There may be movement disorders in the form of ataxia (detect using samples). Although serotonergic antidepressants practically do not affect the cardiovascular system and are even capable of slowing down the heart rhythm, with the development of serotonin syndrome, tachycardia often increases blood pressure.

With weight gain, many patients develop a mania-like state (not to be confused with a possible inversion of affect) with a jump in ideas accelerated by smeared speech, sleep disturbance, hyperactivity, and sometimes confusion and disorientation symptoms. The final stage of serotonin syndrome is very similar to the picture of the ZNS: the body temperature rises sharply, profuse sweat, a masky face, its greasiness appear. Death comes from acute cardiovascular disorders. Such malignant course is extremely rare (individual cases have been described with the combination of SSRI with MAO inhibitors), however, characteristic gastrointestinal and neurological disorders are often encountered in combination therapy with serotonergic drugs, and in combination with MAO inhibitors, according to some data, almost half of patients.

When a serotonin syndrome occurs, the drug should be immediately discontinued and antiserotonin agents should be prescribed to the patient: beta-adrenoblockers (propranolol), benzodiazepines, etc.

Selective inhibitors of reuptake of noradrenaline and serotonin are also called dual-acting drugs. These are the means whose mechanism of action, like classical TA, is associated with the ability to inhibit the reuptake of two neurotransmitters, but they are closer to SSRIs in the tolerability profile. In clinical trials, they have proven themselves as antidepressants with pronounced thymoanaleptic activity.

Venlafaxine has no affinity for M-cholino, a-adreno, or H1-receptors. It has a wide therapeutic range. The blockade of the reuptake of serotonin and norepinephrine is dose-dependent. When using high doses of the drug there is a risk of increasing blood pressure. When cancellation of venlafaxine often occurs withdrawal syndrome.

Duloxetine, like venlafaxine, is devoid of significant affinity for M-cholino, a-adreno or β-receptors. On the effect on noradrenaline transmission, it significantly exceeds other drugs of this group. A powerful effect on norepinephrine metabolism is determined by a less favorable profile of the tolerability of venlafaxine compared with SSRIs because of the risk of developing tachycardia and increasing blood pressure.

Milnacipran has a more powerful effect on noradrenaline transmission than on serotonin. In minimum doses (50 mg / day) milnacipran works as a selective inhibitor of norepinephrine reuptake, but with increasing dose, the serotonergic effect is added. Like other selective inhibitors of the reuptake of serotonin and norepinephrine, milnacipran does not have an affinity for M-cholino, a-adreno or H1 receptors, etc. Milnacipran is similar in profile to SSRIs, but more often it records dizziness, increased sweating and delay urination.

Blockers of pathways of metabolism of neuroamines (monoamine oxidase inhibitors)

MAO - a specific enzyme that catalyzes the oxidative deamination of monoamines, plays a key role in the metabolism and inactivation of serotonin, norepinephrine and partially dopamine. The mechanism of action of MAO inhibitors is the blockade of this enzyme, which leads to a slowing down of the metabolic degradation of monoamine neurotransmitters with an increase in their intracellular content and presynaptic release. The effect of inhibition manifests itself with a single use of drugs. MAO inhibitors also cause deamination of beta-phenylethylamine, dopamine, tyramine, which enter the body with food. Violation of the deamidation of tyramine with nonselective irreversible MAO inhibitors leads to the occurrence of the so-called cheese (or tyramine) syndrome, manifested by the development of hypertensive crisis with the use of foods rich in tyramine (cheese, cream, smoked products, beans, beer, coffee, red wine, yeast, chocolate, beef and chicken liver, etc.). When using nonselective irreversible MAO inhibitors, these foods should be excluded from the diet.

MAO inhibitors are divided into two groups:

• nonselective irreversible MAO inhibitors (nialamide);
• selective reversible MAO inhibitors (pyrlindole, moclobemide, befol, tetryndol).

Clinical experience, which confirmed the severity and potential danger of side effects of irreversible MAO inhibitors (hepatotoxicity, potentiation of pressoric effects of tyramine), associated with prolonged, increasing with the intake or irreversible inhibition of enzyme activity, required the refusal of a wide application of this series. Currently, they are considered only as second-line drugs.

Selective reversible MAO inhibitors have high antidepressant activity, good tolerability and lower toxicity. They are considered as effective as TA and SSRIs, but somewhat less effective than irreversible MAO inhibitors. Among the side effects of these drugs should be noted blurred dry mouth, tachycardia, dyspeptic phenomena; In rare cases, dizziness, headache, anxiety, restlessness and skin allergic reactions may occur. The risk of developing serotonin syndrome with the combination of MAO inhibitors with other antidepressants that increase serotonin levels, such as SSRIs, TA, and specific serotonergic antidepressants, is high. To prevent the development of severe adverse events, it is necessary to observe the interval for the appointment of serotonergic drugs, which depends on the half-life of the drugs used, but at least 2 weeks before and after the administration of irreversible MAO inhibitors. When using MAO inhibitors after fluoxetine, the medication-free interval is increased to 4 weeks. With the appointment of serotonergic drugs after a reversible MAO inhibitor of moclobemide, it can be shortened to 3 days. Restrictions in the diet of tyramine-containing products when using reversible MAO inhibitors are not so stringent, but depend on the dose of the drug. Thus, when moclobemide is used in doses over 900 mg / day, the risk of interactions with tyramine becomes clinically significant.

Pirlindol (pyrazidol) is a domestic antidepressant developed jointly by pharmacologists and psychiatrists of the Research Institute of Psychiatry of the Ministry of Health of the Russian Federation more than 30 years ago. For almost 20 years, the drug has been successfully used to treat depression until the moment when, due to the economic situation, its production was discontinued. After a ten-year hiatus, production resumed in 2002.

This drug is one of the first representatives of selective reversible MAO inhibitors. According to its chemical structure, it belongs to the group of four-cycle antidepressants. Pirlingol discovers the original mechanism of action, having the ability to simultaneously inhibit MAO activity and block the pathways of metabolic destruction of monoamines, selectively deaminating serotonin and adrenaline. In this way, acting on the known neurochemical mechanisms of the onset of depression, the drug realizes its antidepressant properties.

Pirlindol is rapidly absorbed, absorption is slowed by food intake. Bioavailability is 20-30%. More than 95% of the drug binds to blood plasma proteins. The main pathway of metabolism is renal. The pharmacokinetics of pyrrolindol does not show linear dose-dependence. The half-life period ranges from 1.7 to 3.0 h.

The results of scientific research in the first two decades after the creation of pyrlindole showed a significant originality of the drug. In these studies, the undoubted efficacy of pyrlindole with respect to depressive symptoms is shown, a rapid onset of the therapeutic effect and high safety are demonstrated; application. Pyrlindole did not exceed antidepressants of the first generation in terms of the thymoanaleptic effect and even conceded to them in this, but found certain advantages due to the fact that it did not cause an exacerbation of psychotic symptoms, agitation and inversion of affect. The activating effect of pyrlindole was characterized by the mildness of the effect on the symptoms of inhibition and adynamia, did not lead to increased anxiety, agitation and tension. They unanimously recognized the wide spectrum of the therapeutic effect of the drug on the manifestations of depression, in connection with which pyrlinol was called the drug of universal, balanced action. The most interesting feature of the antidepressant action of pyrlindole was a combination of an activating and simultaneously anti-anxiety effect in the absence of hypersedition, drowsiness and increased inhibition, which are known to be characteristic of thiazide diuretics. The noted absence of a sharp dissociation between the activating and anxiolytic action of pyrrolindole caused a harmonious therapeutic effect on the symptoms of depression. At the very beginning of the clinical study of the drug, its dose-dependent effect was seen. Use of the drug in small and medium doses (75-125 mg / day) revealed more clearly its activating effect, with increasing doses (up to 200 mg / day and above), the anti-anxiety component of the action was more obvious.

The return of pirlindole to clinical practice confirmed its relevance and ability to compete with new antidepressants due to the practical absence of cholinolytic side effects, comparatively high efficiency and affordability of the acquisition. From the point of view of the clinician facing the choice of an antidepressant in a specific clinical situation, it is important that pyrlindole has its therapeutic niche, the boundaries of which have expanded significantly due to the fact that it has become more common to detect mild to moderate depression with an atypical picture and the prevalence of anxiety disorders in their structure. The treatment of these widespread disorders is done by both psychiatrists and internists. The purpose of pyrlinodol is completely justified and brings the greatest effect with diffuse, poorly defined or polymorphic depressive syndromes, as well as in unstable states with fluctuations in depth and the variability of the structural components of depression.

In currently conducted studies, the psychopharmacological activity of pyrlindole was evaluated from the standpoint of the concept of positive and negative efficacy in the understanding of AB. Smulevich (2003). It has been shown that in the treatment of depression of the nonpsychotic level, pyrlindole shows significant efficacy in depression with a predominance of positive efficacy (vital, anxiety and senesto-hypochondriacal symptoms). Depression with negative efficacy (apatoadadynamic, depersonalization) significantly responded to treatment with pyrlindole.

In addition to the use of the drug in general psychiatry, it has been shown that pyrlindole can be successfully used to relieve affective disorders associated with the most diverse pathology of internal organs, for example, in the treatment of vegetative and somatized depressions. A good tolerability of the drug was proved in combination of psychic and somatic pathology and the possibility of combining with basic therapy. The drug does not have cardiotoxicity, does not affect the level of blood pressure, heart rate, does not cause orthostatic hypotension and detects protective properties in tissue hypoxia due to circulatory disorders. It is noted that pyrlinol does not enter into clinically significant interaction with the main cardiotropic agents used in the treatment of coronary heart disease.

Treatment with pyrlindole, as a rule, is not accompanied by the development of clinically significant undesirable effects or they are very rare in comparison with those encountered with the use of thiazide diuretics and irreversible MAO inhibitors. Usually, orthostatic hypotension and cardiac arrhythmias are not observed. Deviations in the genital area are not characteristic of some antidepressants. Such cholinolytic effects, such as drowsiness and sedation, are very rare. At the same time, the appointment of pirlingol usually does not lead to an increase or development of insomnia and agitation, rarely causes gastrointestinal disorders. Pyrlindole is not compatible with other MAO inhibitors, including drugs with similar activity (furazolidone, procarbazine, selegiline). When combined with pyrrolidone with adrenomimetics and products containing tyramine, it is possible to enhance the pressor effect. It is undesirable to simultaneously take pyrlindole and thyroid hormones due to the risk of developing hypertension. Pirlingol has the ability to enhance the action of analgesics. The use of pyrlinod at the same time with thiazide diuretics and SSRIs is undesirable, since symptoms of serotonergic hyperactivity may appear, but their prescription immediately after the abolition of pyrlindole is permissible. It has been established that piracetam intensifies the action of pyrlindole, as well as other antidepressants, which can be important in the tactics of counter-resistant therapy of depression. When pyrrolidol is combined with diazepam, the sedative effect of diazepam weakens without decreasing its anxiolytic effect, while the anticonvulsant properties of diazepam are even worse. This interaction of pyrrolindole with diazepam can be used to reduce the side effects of benzodiazepine therapy.

Pirlindol is prescribed orally in tablets of 25 or 50 mg. The initial daily doses are 50-100 mg, increasing the dose is carried out gradually under the control of clinical action and tolerability up to 150-300 mg / day. For treatment of mild to moderate depressions, a daily dose of 100 to 200 mg is usually sufficient, with more severe depressive conditions, the dose of the drug can be increased to 250-300 mg / day. The maximum daily dose is 400 mg. Judgment about the effectiveness of treatment can be made after 3-4 weeks of admission. If a positive result is achieved, preventive therapy should be continued for 4-6 months. Cancellation of the drug is carried out after a gradual dose reduction during the month under the control of the mental state in order to avoid the development of withdrawal syndrome with autonomic symptoms (nausea, anorexia, headache, dizziness).

Toxicological studies have shown that there are no potentially toxic toxic effects of pyrrolindol even after prolonged use of doses exceeding therapeutic ones. There were no clinically significant mutagenic, carcinogenic and clastogenic (induction of chromosomal aberrations) properties.

Thus, the successful past experience of the use of pyrlindole, reproduced in modern studies, confirms the need for its use in the treatment of a wide range of depressions in general psychiatry and somatic medicine.

[9], [10], [11], [12], [13]

Activators of serotonin reuptake

To this group include tianeptine (coaxil), which is a chemical structure of TA, but has a special mechanism of action. As is known, all clinically effective antidepressants cause an increase in the concentration of neurotransmitters, primarily serotonin, in the synaptic space by inhibiting their re-uptake, i.e. Have serotoninase activity. Tianeptine stimulates the seizure of serotonin and therefore has serotonin-negative activity. In addition, a new view on the mechanism of tianeptine has recently appeared. It was suggested that he has neuroprotective effects that enhance the antidepressant activity of this drug. Thus, changes in neurogenesis and neuroplasticity, for example in the hippocampus, can play a significant role in the effectiveness of this antidepressant. According to experimental data, tianeptine exhibits pharmacological properties characteristic of antidepressants. Clinical studies, including the results of comparative multicenter trials, indicate the effectiveness of tianeptine in the treatment of neurotic and hypopsychotic depressions. It is also known that the drug has anxiolytic activity. The advantages of tianeptine include its high safety. It does not cause side-effects of cognitive, psychomotor cardiovascular disorders, sleep disorders, sexual dysfunction and does not affect body weight.

Activators of serotonin reuptake

Mechanism of action	A drug
A2-adrenergic receptor antagonist	Mianserin
Noradrenergic and specific serotonergic antidepressants	Mirtazapine
5-HT3 receptor antagonists and melatonin-1 receptor agonist	Agomelatine

Mianserin (four-cycle antidepressant) has a unique mechanism of action, represented by an increase in the release of norepinephrine due to the blockade of presynaptic a2-adrenergic receptors. These receptors, which stimulate intrasynaptic norepinephrine, in the usual state reduce the release of calcium ions and thereby reduce the calcium-dependent release of norepinephrine. Mianserin, by blocking presynaptic a2-adrenergic receptors, increases the intra-neuronal calcium concentration, which increases the release of norepinephrine. Mianserin has an antidepressant effect, accompanied by anti-anxiety and sedation effects. The characteristic side effects of mianserin, such as orthostatic hypotension and sedation, are associated with the effect of the drug on the a1-adreno-and H1-histamine receptors in the brain.

Mirtazapine (four-cyclic compound) is a noradrenergic specific serotonergic antidepressant. The mechanism of action of the drug is quite complex. Blocking a2-adrenoreceptors, it increases the release of noradrenaline, which leads to an increase in noradrenergic neurotransmission. Increase serotoninovoy transmission occurs through two mechanisms. First, the effect of the drug on a1-adrenoreceptors, which are located on the bodies of cells of serotonergic neurons. Stimulation of these receptors leads to an increase in the release rate of serotonin. Another mechanism of action of mirtazapine is associated with the effect on a2-adrenoreceptors located on the terminals of serotonergic neurons. The drug prevents the inhibitory effect of norepinephrine on serotonergic transmission of influences marked by a moderate affinity of the drug to histamine receptors, as a result of which it may cause drowsiness and an increase in appetite.

Not so long ago, developed agomelatine works simultaneously as a melatonin-1 receptor agonist and as an antagonist of 5-HT2c receptors. The results of preliminary studies give grounds to believe that this drug has anxiolytic activity and is capable of accelerating the resynchronization of the circadian rhythm.

[14], [15], [16], [17], [18], [19], [20], [21], [22], [23]

Clinical classification of antidepressants

The isolation of indications for the differentiated prescription of antidepressants based on the evaluation of the clinical structure is due to the numerous works of domestic psychiatrists.

The basis for the separation of antidepressants using clinical data was originally laid two important components of depressive affect - anxiety and inhibition. So, amitriptyline was regarded as a drug with a predominantly sedative effect, and melipramine was referred to as a means of activating the patient. This approach is not devoid of expediency and it has been used to date in the grouping of antidepressants. An example is the classification proposed by S.N. Mosolov (1996), in which the drugs are divided into three groups: those who have sedative, energizing and balanced action. The expediency of this approach consists in the allocation of clinical "targets" for the purpose of this or that drug. However, according to AC Avedisova (2005), this division is controversial, since it allows one and the same effect of an antidepressant to be considered as therapeutic or as a side effect, depending on the situation. Thus, the tranquilizing and sedative effect (anxiety reduction, improvement of sleep) can be regarded as therapeutic in some patients and as a side effect (drowsiness, lethargy, decreased concentration of attention) in others, and the activating action as therapeutic (increased activity, decreased asthenic manifestations) or as a side effect (irritability, internal tension, anxiety). In addition, this systematization does not distinguish between sedative and anxiolytic effects of antidepressants. Meanwhile, many antidepressants of the new generation - SSRIs, selective stimulators of serotonin reuptake - are practically devoid of sedative properties, but they have a pronounced anxiolytic effect.

Undoubtedly, the development and systematization of antidepressants with the involvement of clinical data is an important area in clinical psychiatry. However, the fact of effectiveness of almost all used antidepressants (first and subsequent generations), which does not exceed 70%, is repeatedly confirmed to date. This is probably due to the fact that depression is a pathogenetically heterogeneous state.

In recent years, work is carried out, focused on the allocation of differentiated indications for the appointment of antidepressants taking into account the pathogenetic features of various components of the depressive state. So, therapy of non-melancholic depression is advisable to start with SSRIs. When registering melancholic depression, it is necessary to use drugs with a dual mechanism of action or TA.

In psychotic depression, it is necessary to expand the receptor effect and to prescribe the agents that affect the dopamine transmission, i.e. It is necessary to combine antidepressants with antipsychotics or use antidepressants that affect dopamine transmission. This approach, of course, to test its effectiveness requires special clinical studies, but it seems promising for the creation of a clinical or even pathogenetic classification.

[24], [25], [26], [27], [28], [29], [30], [31], [32]

Abolition of antidepressants

Sudden discontinuation may lead to withdrawal symptoms that have been described for all types of antidepressants, but are especially common in SSRIs and MAO inhibitors. These symptoms - agitation, sleep disturbance, excessive sweating, unpleasant gastrointestinal sensations and headache - can persist up to 2 weeks. Such symptoms increase the risk of early relapse and may adversely affect the therapeutic alliance. A sudden discontinuation of treatment with TA can lead to a cholinergic syndrome in susceptible patients, especially in the elderly and patients with neurological symptoms.

[33], [34], [35], [36], [37], [38], [39], [40],