Antidepressants

Antidepressants are a group of psychotropic drugs that include synthetic drugs of various chemical structures and drugs of natural origin (for example, derivatives of St. John's wort).

Over almost half a century of clinical use of antidepressants, various methodological approaches have been used to systematize them.

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Pharmacodynamic classification

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

1. Presynaptic neurotransmitter uptake inhibitors.
2. Blockers of metabolic pathways for the destruction of neuroamines.
3. Serotonin reuptake activators.
4. Antidepressants with a receptor mechanism of action.

This division is rather arbitrary, since it reflects only the primary pharmacological action of the antidepressant. For practical work, a total assessment of the drug's pharmacological profile is important, including both the primary point of its application and the nature of its effect on other receptors.

Below is a description of the 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 advantages and disadvantages of a particular 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 division of drugs into two main groups: irreversible MAO inhibitors and TA. It had a certain clinical significance, since at that stage of psychiatry development it was shown that severe endogenous depressions are better treated with thiazide diuretics, and in neurotic depressions, the administration of MAO inhibitors is more effective. Thus, it simultaneously used two principles of dividing drugs, namely, by their chemical structure and the nature of the therapeutic effect. At present, it has more historical significance, although it initially defined the main principles for the subsequent differentiation of antidepressants.

Classification of antidepressants by chemical structure

In the clinical aspect, it is of little information, since it does not give any idea of either the effectiveness or the 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 is included in the citalopram molecule along with the R-enantiomer. After the elimination of R-citalopram, a more powerful effect of the new antidepressant on the reuptake of serotonin was obtained, leading to greater clinical effectiveness and better tolerability compared to its predecessor. The creation of this drug allowed researchers to talk about "allosteric modulation", enhancing the antidepressant effect, with the allocation of a special class of antidepressants - allosteric serotonin reuptake inhibitors.

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Presynaptic neurotransmitter uptake inhibitors

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

In those same years, the first attempts were made to detect a 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 the 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 (increase in the level of neurotransmitters) of antidepressants occurs almost immediately, and the therapeutic effect manifests itself only after 2-3 weeks. Later, it was established that the therapeutic effect of antidepressants is associated not so much with the phenomenon of inhibition of the reuptake of neurotransmitters, but with a change in the sensitivity of synaptic receptors to them. This marked the beginning of the development of adaptive hypotheses of the therapeutic effect of antidepressants. Studies have shown that chronic use of most antidepressants causes a number of changes in postsynaptic membranes, such as a decrease in the density of serotonin 5-HT2 and a2-adrenergic receptors, an increase in the number of GABA-ergic receptors, etc. One of the new concepts suggests that depression is the result of disruption of neural networks, and the work of antidepressants is to improve information processes in damaged networks. The basis of damage to these networks is a violation of neuroplasticity processes. Thus, it turned out that long-term 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 when they are prescribed 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 followed the path of creating drugs with a similar chemical structure, which are still traditionally called tricyclic antidepressants.

There are differences in terminology in English- and Russian-language literature. Thus, in Russian literature, the term "tricyclic antidepressants" (TA) refers to antidepressants of only a tricyclic structure, while in English-language literature, the TA group includes drugs of both tricyclic and tetracyclic structures. This approach is artificial to a certain extent, since drugs with tri- and tetracyclic structures differ not only in chemical structure, but also in their mechanism of action. For example, the tetracyclic antidepressant mianserin has a unique mechanism of action, according to which it increases the release of norepinephrine by blocking presynaptic a2-adrenoreceptors.

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

Classic tricyclic antidepressants, depending on the number of methyl groups on the nitrogen part - the side chain, are divided into secondary and tertiary amines. Tertiary amines include amitriptyline, imipramine and clomipramine; secondary amines include nortriptyline and desipramine. Tertiary amines are considered to have a greater affinity for serotonin receptors, while secondary amines have a greater affinity for noradrenergic receptors. Clomipramine has the greatest effect on the reuptake of serotonin from the group of classical tricyclic antidepressants. All drugs related to tertiary amines have approximately the same effect on the reuptake of norepinephrine. Some authors consider it expedient to isolate tricyclic antidepressants with predominant serotonergic (S-TA) and noradrenergic (N-TA) action. According to S.N. According to Mosolova (1995), the clinical significance of such a division is questionable, and this is due not only to the fact that the noradrenergic and serotonergic systems are closely related to each other, but also to the fact that most TAs are not selective and block the presynaptic uptake of norepinephrine and serotonin almost equally. This is confirmed by the fact that tertiary amines are metabolized in the body to secondary amines. The active metabolites of these drugs - desipramine, nortriptyline and desmethylclomipramine, affecting norepinephrine transmission - participate in the integral antidepressant effect of the drug. Thus, most traditional TAs are drugs that affect both the reuptake of serotonin and norepinephrine. All representatives of this group of antidepressants have a very insignificant effect on the reuptake of dopamine. At the same time, they are compounds with a broad neurochemical profile and are capable of causing many secondary pharmacodynamic effects. They can affect not only the uptake of monoamines, but also the central and peripheral muscarinic cholinergic receptors, a2-adrenoreceptors and histamine receptors, which is associated with most of the side effects of therapy.

The side effects of classical tricyclic antidepressants are varied.

Dry mouth, mydriasis, increased intraocular pressure, accommodation disorder, tachycardia, constipation (up to paralytic ileus) and urinary retention are associated with the peripheral anticholinergic action of TA.

In this regard, the drugs are contraindicated in glaucoma, prostate hyperplasia. Peripheral anticholinergic effects are dose-dependent and disappear after the drug dose is reduced.

The central anticholinergic effect of these antidepressants is associated with the possible development of delirium and seizures when taking them. These side effects also have a dose-dependent effect. In particular, the risk of developing delirium increases with amitriptyline concentrations in the blood exceeding 300 ng/ml, and occurs significantly more often when the concentration reaches 450 ng/ml when taking amitriptyline. Anticholinergic effects can also contribute to the development of tachycardia.

The sedative effect is associated with the blockade of histamine H1 receptors by these antidepressants. It can be used to treat sleep disorders associated with depression, but daytime sleepiness often complicates therapy and causes patients to have a negative attitude towards taking medications. Drugs with a sedative effect are appropriate to prescribe to patients with severe anxiety in the early stages of therapy, but at later stages, excessive sedation makes it difficult to adequately assess the patient's condition.

Classical TA have pronounced cardiotoxicity, which manifests itself as conduction disturbances in the atrioventricular node and ventricles of the heart (quinine-like effect), arrhythmias, and decreased myocardial contractility.

With long-term use of classical TA, an increase in appetite is possible, and subsequently an increase in body weight, which increases the already high risk of developing metabolic syndrome in depression.

A serious reason why one should be very careful when prescribing classical TA is the frequency of completed suicides associated with drug overdose. The literature has noted a direct link between the use of these drugs and the fatal outcome of suicide attempts.

Side effects of therapy require caution when prescribing classical TA. According to modern standards of depression therapy developed by WHO experts, these drugs are not first-line drugs and their use is recommended only in hospital settings for two reasons. Firstly, due to a large number of various side effects. Secondly, when prescribing classical TA, titration of the dose is necessary. Before prescribing these drugs, patients should undergo an examination to exclude clinically significant somatic disorders. Given the pronounced cardiotoxic effect, an ECG is necessary before prescribing drugs of this group. Patients with a QT interval greater than 450 ms represent a risk group for developing complications from the cardiovascular system, so the use of these drugs is undesirable; the presence of glaucoma or prostate adenoma is also a contraindication for prescribing classical TA.

SSRIs are a group of drugs that are heterogeneous in chemical structure (mono-, di- and multicyclic compounds), but have a common mechanism of action. The 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 in the treatment of depressive spectrum disorders (obsessive-compulsive, anxiety and phobic disorders, social phobia, etc.). SSRIs in modern global clinical practice are first-line drugs in the treatment of depression. This group includes 6 antidepressants: fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram.

Fluoxetine has the strongest inhibitory effect on 5-HT2c receptors of all SSRIs. Inhibition of these receptors affects the activity of the norepinephrine and dopamine systems. This effect determines the activating properties of the drug, which are expressed to a greater extent than in other SSRIs. From a clinical point of view, this effect can be characterized as uncertain. On the one hand, the effect of the drug on 5-HT2c receptors can cause insomnia, increased anxiety, and the development of agitation. On the other hand, this pharmacological effect is desirable in patients with hypersomnia, inhibition, and apathoanergic depressions.

Sertraline, unlike other antidepressants of this group, has the ability to block the reuptake of dopamine, but weaker than inhibition of the reuptake of serotonin. The effect on the reuptake of dopamine occurs when using the drug in high doses. The result of the affinity for dopamine receptors is its ability to cause extrapyramidal symptoms. Sertraline is effective in the treatment of melancholic, prolonged depression, and psychotic depression.

Fluvoxamine has a unique clinical effect, which can be explained 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 advisable to use it in patients engaged in mental work.

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

Citalopram has the highest affinity for histamine H1 receptors compared to other SSRIs. The drug's affinity for H1 receptors, for example, is more than 100 times greater than that of fluvoxamine. This is related to citalopram's ability to increase carbohydrate cravings and thus contribute to the development of obesity.

Escitalopram is the active S-enantiomer of citalopram. Escitalopram has a slightly different mechanism of action than other serotonergic antidepressants: it interacts not only with the primary binding site of the serotonin transporter protein, but also with the secondary (allosteric) site, which leads to a more rapid, 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 compared to citalopram.

Side effects of SSRIs are associated with the effect on serotonin transmission. Serotonin receptors are widely present in the central and peripheral nervous system, as well as in organs and tissues (smooth muscles of the bronchi, gastrointestinal tract, vascular walls, etc.). The most common side effects are gastrointestinal disorders: nausea, less often vomiting, diarrhea (due to excessive stimulation of 5-HT3 receptors of serotonin subtype 3). These disorders 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 begin therapy with low daily doses of drugs, followed by an increase by the 4th-5th day of treatment.

Excitation of serotonin receptors may be accompanied by tremor, hyperreflexia, impaired coordination of movements, dysarthria, headache. Approximately 30% of patients taking SSRIs (especially paroxetine, sertraline) experience sexual dysfunction, expressed in weakening of erection, delayed ejaculation, partial or complete anorgasmia, which often leads to refusal to continue therapy. These adverse events are also dose-dependent and when they occur, a reduction in the drug dose is recommended.

The most dangerous complication of therapy with these antidepressants is "serotonin syndrome". According to S.N. Mosolov et al. (1995), the initial manifestations of serotonin syndrome affect mainly the gastrointestinal and nervous systems of the body. Initially, there is rumbling, abdominal colic, flatulence, loose stools, nausea, less often vomiting and other dyspeptic phenomena. Neurological symptoms include extrapyramidal symptoms (tremor, dysarthria, restlessness, muscle hypertonia), hyperreflexia and myoclonic twitching, which usually begin in the feet and spread throughout the body. Movement disorders in the form of ataxia may occur (detected using tests). Although serotonergic antidepressants have virtually no effect on the cardiovascular system and are even capable of slowing the heart rate, with the development of serotonin syndrome, tachycardia and increased blood pressure are often observed.

With worsening of the general condition, many patients develop a manic-like state (not to be confused with possible affect inversion) with a flight of ideas, accelerated slurred speech, sleep disturbances, hyperactivity, and sometimes with confusion and symptoms of disorientation. The final stage of serotonin syndrome is very reminiscent of the picture of NMS: body temperature rises sharply, profuse sweating, a mask-like face, and its greasiness appear. Death occurs from acute cardiovascular disorders. Such a malignant course is extremely rare (isolated cases have been described with a combination of SSRIs with MAO inhibitors), but characteristic gastrointestinal and neurological disorders are quite common with combined therapy with serotonergic drugs, and in combination with MAO inhibitors, according to some data, in almost half of patients.

If serotonin syndrome occurs, the drug must be discontinued immediately and the patient must be prescribed antiserotonin drugs: beta-blockers (propranolol), benzodiazepines, etc.

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

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

Duloxetine, like venlafaxine, lacks significant affinity for M-cholinergic, a-adreno-, or ^-receptors. In terms of its effect on norepinephrine transmission, it significantly surpasses other drugs in this group. The powerful effect on norepinephrine metabolism determines the less favorable tolerability profile of venlafaxine compared to SSRIs due to the risk of developing tachycardia attacks and increased blood pressure.

Milnacipran has a more powerful effect on norepinephrine transmission than on serotonin. In minimal doses (50 mg/day), milnacipran acts as a selective norepinephrine reuptake inhibitor, but with increasing doses, a serotonergic effect is added. Like other selective serotonin and norepinephrine reuptake inhibitors, milnacipran has no affinity for M-cholinergic, a-adreno- or H1-receptors, etc. In terms of side effect profile, milnacipran is similar to SSRIs, but dizziness, increased sweating, and urinary retention are more often recorded.

Neuroamine metabolic pathway blockers (monoamine oxidase inhibitors)

MAO is 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 consists in blocking this enzyme, which leads to a slowdown in the metabolic degradation of monoamine neurotransmitters with an increase in their intracellular content and presynaptic release. The inhibition effect is already evident with a single use of the drugs. MAO inhibitors also cause deamination of beta-phenylethylamine, dopamine, and tyramine, which enter the body with food. Disruption of tyramine deamination by non-selective irreversible MAO inhibitors leads to the so-called cheese (or tyramine) syndrome, which manifests itself in the development of a hypertensive crisis when consuming foods rich in tyramine (cheese, cream, smoked meats, legumes, beer, coffee, red wines, yeast, chocolate, beef and chicken liver, etc.). When using non-selective irreversible MAO inhibitors, these products must be excluded from the diet.

MAO inhibitors are divided into two groups:

• non-selective irreversible MAO inhibitors (nialamide);
• selective reversible MAO inhibitors (pirlindol, moclobemide, befol, tetrindol).

Clinical experience, which confirmed the severity and potential danger of the side effects of irreversible MAO inhibitors (hepatotoxicity, potentiation of the pressor effects of tyramine), associated with long-term, increasing with intake or irreversible inhibition of enzymatic activity, required the abandonment of the widespread use of drugs of this series. At present, 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 SSRI, but somewhat less effective than irreversible MAO inhibitors. Among the side effects of these drugs, it is necessary to note mild dry mouth, tachycardia, dyspeptic phenomena; in rare cases, dizziness, headache, anxiety, restlessness and skin allergic reactions may occur. There is a high risk of developing serotonin syndrome when combining MAO inhibitors with other antidepressants that increase serotonin levels - SSRI, TA, specific serotonergic antidepressants. To prevent the development of severe adverse effects, it is necessary to observe an interval when prescribing serotonergic drugs, which depends on the half-life of the drugs used, but not less than 2 weeks before and after prescribing irreversible MAO inhibitors. When using MAO inhibitors after fluoxetine, the drug-free interval is increased to 4 weeks. When prescribing serotonergic drugs after the reversible MAO inhibitor moclobemide, it can be reduced to 3 days. Dietary restrictions on tyramine-containing products when using reversible MAO inhibitors are not so strict, but depend on the dose of the drug. Thus, when using moclobemide in doses above 900 mg/day, the risk of interactions with tyramine becomes clinically significant.

Pirlindol (Pirazidol) is a domestic antidepressant developed more than 30 years ago jointly by pharmacologists and psychiatrists of the Research Institute of Psychiatry of the Ministry of Health of the Russian Federation. For almost 20 years, the drug was successfully used to treat depression until its production was discontinued due to the economic situation. After a ten-year break, production was 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 tetracyclic antidepressants. Pirlindol exhibits an original mechanism of action, possessing the ability to simultaneously inhibit MAO activity and block the pathways of metabolic destruction of monoamines, selectively deaminating serotonin and adrenaline. By acting in this way on the currently known neurochemical mechanisms 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 plasma proteins. The main metabolic pathway is renal. The pharmacokinetics of pirlindol does not show linear dose dependence. The half-life ranges from 1.7 to 3.0 hours.

The results of scientific research in the first two decades after the creation of pirlindol demonstrated significant uniqueness of the drug. These studies demonstrated the undoubted effectiveness of pirlindol in relation to depressive symptoms, a fairly rapid onset of therapeutic effect and high safety; application. Pirlindol did not exceed first-generation antidepressants in the power of thymoanaleptic effect and was even inferior to them in this, but showed certain advantages due to the fact that it did not cause an exacerbation of psychotic symptoms, agitation and affect inversion. The activating effect of pirlindol was characterized by a soft effect on the symptoms of inhibition and adynamia, did not lead to increased anxiety, agitation and tension. A wide range of therapeutic effects of the drug on the manifestations of depression was unanimously recognized, in connection with which pirlindol was called a drug of universal, balanced action. The most interesting feature of the antidepressant action of pirlindol was the combination of an activating and simultaneously anti-anxiety effect in the absence of hypersedation, 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 pirlindol determined the harmonious therapeutic effect on the symptoms of depression. Already at the very beginning of the clinical study of the drug, its dose-dependent effect was noted. The use of the drug in small and medium doses (75-125 mg / day) revealed its activating effect more clearly, with an increase in the dose (up to 200 mg / day and higher) the anti-anxiety component of the action was more obvious.

The return of pirlindol to clinical practice has confirmed its demand and the ability to compete with new antidepressants due to the virtual absence of anticholinergic side effects, relatively high efficiency and availability. From the point of view of a clinician faced with the choice of an antidepressant in a specific clinical situation, it is important that pirlindol has its own therapeutic niche, the boundaries of which have expanded significantly due to the fact that mild and moderate depressions with an atypical picture and prevalence of anxiety-hypochondriacal disorders in their structure have become more common. Both psychiatrists and internists are involved in the treatment of these widespread disorders. The prescription of pirlindol is completely justified and brings the greatest effect in case of vague, insufficiently clearly defined or polymorphic depressive syndromes, as well as in unstable conditions with fluctuations in depth and variability of the structural components of depression.

In studies conducted to date, the psychopharmacological activity of pirlindol was assessed from the standpoint of the concept of positive and negative efficacy as understood by A.B. Smulevich (2003). It was shown that in the treatment of non-psychotic depressions, pirlindol exhibits reliable efficacy in depressions with a predominance of positive efficacy (vital, anxious, and senesto-hypochondriac symptoms). Depressions with negative efficacy (apatoadynamic, depersonalization) responded significantly worse to treatment with pirlindol.

In addition to the use of the drug in general psychiatry, it has been shown that pirlindol can be successfully used to relieve affective disorders associated with a wide variety of pathologies of internal organs, for example, in the treatment of vegetative and somatized depressions. Good tolerability of the drug in combination with mental and somatic pathology and the possibility of combining with basic therapy have been proven. The drug does not have cardiotoxicity, does not affect blood pressure, heart rate, does not cause orthostatic hypotension and exhibits protective properties in conditions of tissue hypoxia due to circulatory disorders. It is noted that pirlindol does not enter into clinically significant interactions with the main cardiotropic agents used in the treatment of coronary heart disease.

Treatment with pirlindol is usually not accompanied by the development of clinically significant adverse effects or they are very rare compared to those observed with the use of thiazide diuretics and irreversible MAO inhibitors. Orthostatic hypotension and cardiac arrhythmia are usually not observed. Sexual deviations typical of some antidepressants are not noted. Anticholinergic effects such as drowsiness and sedation are very rare. At the same time, the administration of pirlindol usually does not lead to an increase or development of insomnia and agitation, and rarely causes gastrointestinal disorders. Pirlindol is incompatible with other MAO inhibitors, including drugs with similar activity (furazolidone, procarbazine, selegiline). When pirlindol is used together with adrenomimetics and products containing tyramine, an increase in the pressor effect is possible. It is not advisable to take pirlindol and thyroid hormones at the same time due to the risk of developing arterial hypertension. Pirlindol has the ability to enhance the effect of analgesics. The use of pirlindol simultaneously with thiazide diuretics and SSRIs is undesirable, since symptoms of serotonergic hyperactivity may occur, but their use is permissible immediately after discontinuing pirlindol. It has been established that piracetam enhances the effect of pirlindol, as well as other antidepressants, which may be important in the tactics of anti-resistant depression therapy. When combining pirlindol with diazepam, the sedative effect of diazepam weakens without reducing its anxiolytic effect, while the anticonvulsant properties of diazepam even increase. This interaction of pirlindol 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, the dose is gradually increased under the control of the clinical effect and tolerability to 150-300 mg / day. For the treatment of mild and moderate depression, a daily dose of 100-200 mg is usually sufficient, in more severe depressive states, the dose of the drug can be increased to 250-300 mg / day. The maximum daily dose is 400 mg. Judgment on the effectiveness of treatment can be made after 3-4 weeks of administration. If a positive result is achieved, preventive therapy should be continued for 4-6 months. The drug is discontinued after a gradual dose reduction over a month under the control of the mental state in order to avoid the development of withdrawal syndrome with vegetative symptoms (nausea, anorexia, headache, dizziness).

Toxicological studies have shown the absence of potentially dangerous toxic effects of pirlindol even with prolonged use of doses exceeding therapeutic ones. No clinically significant mutagenic, carcinogenic or clastogenic (induction of chromosomal aberrations) properties were detected.

Thus, the successful past experience of using pirlindole, 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.

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Serotonin reuptake activators

This group includes tianeptine (coaxil), which is a TA by its chemical structure, 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 reuptake, i.e. they have serotonin-positive activity. Tianeptine stimulates serotonin uptake and, therefore, has serotonin-negative activity. In addition, a new look at the mechanism of action of tianeptine has appeared relatively recently. It has been suggested that it 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 cognitive, psychomotor cardiovascular disorders, sleep disorders, sexual dysfunction and does not affect body weight.

Serotonin reuptake activators

Mechanism of action	Preparation
α2-adrenergic receptor antagonist	Mianserin
Noradrenergic and specific serotoninergic antidepressants	Mirtazapine
5-HT3 receptor antagonists and melatonin-1 receptor agonist	Agomelatine

Mianserin (a tetracyclic antidepressant) has a unique mechanism of action, which is represented by an increase in the release of norepinephrine due to the blockade of presynaptic a2-adrenoreceptors. These receptors, which are stimulated by intrasynaptic norepinephrine, in the normal state reduce the release of calcium ions and thereby reduce the calcium-dependent release of norepinephrine. Mianserin, by blocking presynaptic a2-adrenoreceptors, increases the intraneuronal concentration of calcium, which enhances the release of norepinephrine. Mianserin has an antidepressant effect, accompanied by anti-anxiety and sedative effects. Characteristic side effects of mianserin, such as orthostatic hypotension and sedative effect, are associated with the effect of the drug on the a1-adreno- and H1-histamine receptors of the brain.

Mirtazapine (a tetracyclic compound) is a noradrenergic specific serotonergic antidepressant. The mechanism of action of the drug is quite complex. By blocking a2-adrenoreceptors, it increases the release of norepinephrine, which leads to increased noradrenergic neurotransmission. Increased serotonin transmission occurs through two mechanisms. Firstly, this is the effect of the drug on a1-adrenoreceptors, which are located on the cell bodies of serotonergic neurons. Stimulation of these receptors leads to an increase in the rate of serotonin release. 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. Moderate affinity of the drug to histamine receptors is noted, as a result of which drowsiness and increased appetite may occur when taking it.

The recently developed agomelatine acts both as a melatonin-1 receptor agonist and as a 5-HT2c receptor antagonist. Preliminary studies suggest that this drug has anxiolytic activity and is capable of forcing circadian rhythm resynchronization.

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Clinical classification of antidepressants

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

The classification of antidepressants using clinical data was initially based on two important components of depressive affect - anxiety and inhibition. Thus, amitriptyline was regarded as a drug with a predominantly sedative effect, and melipramine was classified as a drug that activates the patient. This approach is not without expediency and has been used to date in grouping antidepressants. An example is the classification proposed by S.N. Mosolov (1996), in which drugs are divided into three groups: those with a sedative, activating, and balanced effect. The expediency of this approach is to identify clinical "targets" for prescribing a particular drug. However, according to A.S. Avedisova (2005), such a division is quite controversial, since it allows one and the same antidepressant effect to be considered as therapeutic or as a side effect depending on the situation. Thus, the tranquilizing and sedative effect (reduction of anxiety, improvement of sleep) can be regarded as therapeutic in some patients and as a side effect (drowsiness, lethargy, decreased concentration) in others, and the activating effect can be regarded as therapeutic (increased activity, decreased asthenic manifestations) or as a side effect (irritability, internal tension, anxiety). In addition, this systematization does not differentiate between the sedative and anxiolytic effects of antidepressants. Meanwhile, many new generation antidepressants - SSRIs, selective serotonin reuptake stimulants - are practically devoid of sedative properties, but have a pronounced anxiolytic effect.

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

In recent years, work has been carried out aimed at identifying differentiated indications for prescribing antidepressants, taking into account the pathogenetic features of various components of the depressive state. Thus, it is advisable to begin therapy for non-melancholic depression 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 prescribe agents that affect dopamine transmission, i.e. it is necessary to combine antidepressants with antipsychotics or use antidepressants that affect dopamine transmission. This approach, of course, requires special clinical studies to verify its effectiveness, but it seems promising for creating a clinical or even pathogenetic classification.

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Antidepressant withdrawal

Abrupt discontinuation of medication may result in withdrawal symptoms, which have been described for all types of antidepressants but are particularly characteristic of SSRIs and MAOIs. These symptoms - agitation, sleep disturbance, increased sweating, gastrointestinal discomfort, and headache - may persist for up to 2 weeks. Such symptoms increase the risk of early relapse and may negatively affect the therapeutic alliance. Abrupt discontinuation of TA treatment may result in the emergence of cholinergic syndrome in susceptible patients, especially the elderly and patients with neurological symptoms.

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