Anxiety Disorders

At present, the widely accepted view is that anxiety disorders are a group of close, but at the same time, different psychopathological conditions. It was reflected in relatively small changes in the main categorization of anxiety disorders that were introduced in the fourth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM), compared to the third revision of the DSM. According to DSM-W, the primary "anxiety disorders" are nine states: panic disorder with agoraphobia and without agoraphobia; agoraphobia without panic disorder; specific phobias; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder and generalized anxiety disorder.

[1], [2], [3]

Causes of the anxiety disorders

The causes of the development of anxiety disorders are completely unknown, both psychic and somatic factors matter. Many people develop anxiety disorders without clear triggers. Anxiety can be a response to external stressors, such as ending important relationships or having a life-threatening hazard. Some somatic diseases in themselves cause anxiety, for example, hyperthyroidism, pheochromocytoma, hyperadrenocorticism, heart failure, arrhythmias, bronchial asthma and chronic obstructive pulmonary disease (COPD). Other physical reasons include the use of drugs; effects of glucocorticoids, cocaine, amphetamines and even caffeine can mimic anxiety disorders. The abolition of alcohol, sedatives and some banned psychoactive substances can also be troubling.

[4], [5]

Pathogenesis

Every person periodically experiences fear and anxiety. Fear is an emotional, somatic and behavioral response to a directly recognizable external threat (for example, an attack or the risk of a car accident). Anxiety is an unpleasant emotional state of nervousness and anxiety; its causes are not as obvious as in fear.

Anxiety is less time-related with a threat, it can anticipate a threat, or persist, after the danger disappears, or manifest itself in the absence of a certain threat. Anxiety is often accompanied by somatic changes and behavior similar to that of fear.

A certain degree of anxiety is adaptive, it allows you to prepare and improve the level of functioning of the body, which allows a person to be more careful in potentially dangerous situations. However, exceeding a certain level, anxiety causes malfunctions and marked distress. In this situation, anxiety is disadaptive and is seen as a disorder.

Anxiety occurs with various mental and physical illnesses, but with some of them is the dominant symptom. Anxiety disorders are more common than other types of mental pathology. However, sometimes they are not recognized and, as a consequence, are not treated. The chronic disadaptable anxiety that remains untreated can aggravate or hinder the treatment of a number of somatic diseases.

In the medical literature, the term "anxiety" is understood as fear or fear that is excessive in relation to a specific life situation. Thus, the extreme degree of fear or fear is defined as a "pathological anxiety" if they are inadequate to the level of a person's development - for example, the fear of leaving a high school student's home, or personal life circumstances - for example, the fear of losing a job in a person who successfully copes with it. Clinical studies of the last 30 years have been accompanied by constant improvement of the notion of the nosological structure of anxiety disorders. At the beginning of the 20th century, the understanding of anxiety disorders was rather vague, but over time, the place of anxiety disorders among other mental disorders was more clearly defined, partly influenced by pharmacological studies.

[6], [7], [8], [9], [10], [11], [12], [13], [14]

Symptoms of the anxiety disorders

Anxiety can occur suddenly, like a panic, or grow gradually over minutes, hours and even days. Anxiety can last from a few seconds to several years, longer duration is more typical for anxiety disorders. Anxiety varies from subtle anxiety to panic.

Anxiety disorders can be accompanied by depression and exist simultaneously, or depression can develop first, and symptoms of anxiety disorder may appear later.

The decision about whether the anxiety is so dominant and pronounced, what constitutes a disorder, is determined by a number of factors. The doctor assesses the extent to which they determine the diagnosis. First of all, the doctor must find out, on the basis of anamnesis, physical examination and appropriate laboratory tests, whether anxiety is the result of a physical illness or the use of psychoactive substances. It is also necessary to determine whether anxiety is a symptom of another mental disorder. If there are no other causes of anxiety, if the anxiety causes significant distress and disrupts functioning, does not go through spontaneously in a few days, then there is likely to be an anxiety disorder that requires treatment.

[15], [16], [17]

Diagnostics of the anxiety disorders

Diagnosis of a specific anxiety disorder is based on characteristic symptoms and signs. Having a family history of anxiety disorders (excluding acute and post-traumatic stress disorder) helps in establishing the diagnosis, as some patients have a hereditary predisposition to the same anxiety disorders as the relatives, and a general predisposition to the development of anxiety disorders. However, in some patients, the same disorders can occur, as in their relatives, through the mechanism of adopting behavioral patterns.

[18], [19],

Treatment of the anxiety disorders

It should be especially emphasized the importance of diagnosis of comorbid conditions. For example, patients with anxiety disorder often experience depression, only when it is recognized and corrected, treatment will be successful. In addition, anxiety disorders are often complicated by the formation of dependence on psychotropic drugs, which requires a special approach to treatment. Another example: with uncomplicated generalized anxiety disorder, the drug of choice may be benzodiazepines, but they are ineffective if generalized anxiety disorder is combined with major depression and is not appropriate in patients who abuse psychotropic substances.

Selection of treatment of anxiety disorders requires also taking into account the somatic status of the patient. All patients with a recent anxiety should undergo a thorough physical examination to identify signs of somatic or neurological diseases that can cause symptoms of anxiety disorders. Importantly, the choice of therapy is also carefully collected history of the drugs that the patient is currently taking and that he has taken in the past. If you suspect a misuse of psychotropic drugs, you need a laboratory test. Usually, there is no need for consulting a neurologist, but neurological examination requires a thorough neurological examination if symptoms are found.

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors are a unique class of drugs. Prior to their creation in the 1980s, the search for new drugs for the treatment of anxiety, as well as most other mental disorders, was carried out empirically - on the basis of random clinical observations. Psychotropic drugs developed before SSRIs operated on many neurotransmitter systems. On the contrary, SSRIs were created in such a way as to selectively act only on the zone of presynaptic reuptake of serotonin in the endings of serotonergic neurons. This choice was predetermined by observations that showed that the common property of drugs effective in anxiety and depression is the ability to inhibit the reuptake of serotonin in the brain.

The effectiveness of SSRIs in the therapy of anxiety and depression indicated the important role of serotonin in the pathogenesis of these conditions. This led to the creation of new models of mental disorders on laboratory animals and gave a new direction to genetic research in humans. The effectiveness of SSRIs in a wide range of mental disorders also stimulated the search for similarities and differences in the neurochemical basis of anxiety and depressive disorders. In clinical practice, SSRIs have gained wide popularity, since they combine high efficiency with a variety of mental disorders with good tolerability and safety.

Currently, there are five drugs related to SSRIs: fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram. The sixth drug, zimelidine, was withdrawn, as several cases of Guillain-Barre syndrome were noted against its background. This chapter gives a general description of all five drugs as a single group, individual differences in drugs are emphasized only when they are of clinical importance.

Several large, randomized controlled clinical trials have demonstrated the efficacy of SSRIs in the treatment of acute episodes of various types of anxiety disorders. If we do not consider obsessive-compulsive disorder, then the greatest experience with the use of SSRIs is accumulated in panic disorder. In this condition, the effectiveness of fluvoxamine, paroxetine, sertraline, citalopram was noted. Although there is almost no data on the comparative efficacy of various SSRIs, it can be assumed that they are all equally effective in panic disorder. The differences between the preparations relate mainly to the duration of the half-elimination period and the ability to interact with other drugs. The latter feature is mainly dependent on differences in the effect on hepatic enzymes that metabolize drugs.

There are only a few publications on the effectiveness of SSRIs in other anxiety disorders (in addition to panic disorder). Two of three small studies have demonstrated the efficacy of fluvoxamine and sertraline in social phobia, while paroxetine has yielded less definitive results. One study showed the effectiveness of fluoxetine in PTSD, and it proved to be effective in the aftermath of injuries to the civilian population, but not in veterans of wars. There are no publications on the effectiveness of SSRIs in isolated generalized anxiety disorder. Although the data on the effectiveness of most SSRIs have been accumulated in panic disorder, only for paroxetine this indication is approved by the FDA.

SSRIs have proven effective in the treatment of major depression and dysthymia, which are often combined with panic disorder. Moreover, controlled clinical trials of SSRIs in anxiety disorders have not always excluded patients with comorbid affective symptoms. Therefore, it remains unclear to which of the groups of anxious SSRIs are more effective: in patients with or without comorbid depression. It is known that SSRIs are able to prevent a relapse of major depression, but only in a few studies this property has been studied in the appendix to anxiety disorders. Nevertheless, SSRIs are prescribed for the prevention of relapses of anxiety disorders for months and years, when they have proved effective in treating acute episodes.

There have been few direct comparative studies of the efficacy of SSRIs and other drugs effective in anxiety disorders. Clinicians often prefer SSRIs to tricyclic antidepressants, MAO inhibitors and benzodiazepines, since they have a more favorable profile of side effects, they do not cause drug dependence, and do not pose a serious danger in overdose.

SSRIs inhibit the reuptake of serotonin in the presynaptic ending. Numerous scientific studies confirm that this mechanism is associated with their antidepressant effect. In particular, it has been shown that drugs inhibiting the reuptake of serotonin are effective on models of depression in animals. The results of studies on animal anxiety models were more variable, but this can be attributed to the inadequacy of the model itself. For example, it remains unclear whether the experiment with the creation of the "approach-avoidance" conflict situation can serve as a model of panic disorder.

It is generally recognized that the blockade of serotonin reuptake is at the heart of the therapeutic effect of SSRIs, but it remains unclear how this neurochemical mechanism leads to clinical improvement. Therefore, the therapeutic effect of SSRIs, both in experimental animals and in humans, appears only after many days. Apparently, it can not be explained directly by the blockade of the reverse capture, which develops immediately. It is assumed that with prolonged administration of the drug, the effect of serotonergic neurons of the suture nuclei on the prefrontal cortex and limbic structures is enhanced. But how this relates to the reduction of anxiety and depressive disorders in humans remains unknown.

The main advantage of SSRIs over other drugs is a more favorable profile of side effects. It is especially important that SSRIs have minimal effect on the cardiovascular system. In contrast, tricyclic antidepressants can cause cardiac conduction abnormalities and a drop in blood pressure. The most common side effects of SSRIs include irritability and anxiety, which can disturb sleep (especially if treatment starts with high doses), as well as headache. Often observed and gastrointestinal disorders: nausea, constipation, diarrhea, anorexia. One of the most unpleasant aspects of using SSRIs is that they often cause sexual dysfunction in both sexes, in particular - a decrease in libido and anorgasmia. Rare side effects include urinary retention, sweating, visual impairment, akathisia, dizziness, fatigue, and motor impairment. Like other antidepressants, SSRIs can provoke mania. Since direct comparative studies of the risk of developing mania with the use of antidepressants of various groups have not been carried out, it remains unclear whether SSRIs are safer in this respect or not.

There are practically no absolute contraindications to the use of SSRIs. Nevertheless, they should be combined with caution with other drugs. SSRIs inhibit the activity of various isoenzymes of cytochrome P450, a family of hepatic enzymes that metabolize many drugs. As a result, the concentration in the blood of certain drugs, if they are prescribed together with SSRIs, can reach toxic levels. For example, this occurs with a combination of tricyclic antidepressants with fluoxetine or sertraline, theophylline or haloperidol with fluvoxamine, phenytoin with fluoxetine. Nevertheless, SSRIs can be combined with a tricyclic antidepressant, but subject to regular monitoring of the concentration of the tricyclic drug in the blood. At the same time, combinations of SSRIs with MAO inhibitors should be avoided due to the risk of serious side effects, such as serotonin syndrome. In any case, before appointing SSRIs, it should be consulted in relevant publications about the possibility of their interaction with other drugs that the patient takes.

SSRIs do not cause serious complications, even if their dose is five or ten times the therapeutic dose. Although, in this case, adults can be excited, vomited, occasionally - epileptic seizures, not a single lethal outcome with an overdose of only one SSRI is not recorded. At the same time, two fatal outcomes are described, following the administration of high doses of fluoxetine (not less than 1800 mg) in combination with other drugs.

Azapirones

Azapirones are a class of drugs with a high affinity for serotonin 5-HT1A receptors located on the body and in the endings of serotonergic neurons, as well as in dendrites of postsynaptic neurons with which serotonergic endings come into contact. This group includes three drugs: buspirone, gepirone, ipsapirone. On laboratory anxiety models in animals, azapirones act like benzodiazepines, although their effect is less pronounced. Apparently, this effect is due to the fact that they are partial agonists of presynaptic 5-HT1A receptors. The efficacy of azapiron is also shown in models of depression in animals.

Buspirone is registered as a drug for the treatment of generalized anxiety disorder. As in the case of SSRIs, the effect of buspirone in generalized anxiety disorder is manifested only after several days of constant admission. Buspirone is not inferior in effectiveness to benzodiazepines in this disease, although it does not function as fast as they do (Rickels et al., 1988). A randomized clinical trial demonstrated the efficacy of buspirone even in severe depression, especially if accompanied by severe anxiety; However, the validity of these results was questioned because of the large number of patients who left the study. In a randomized study, it was also shown that buspirone reduces the anxiety of alcoholics suffering from comorbid generalized anxiety disorder after detoxification.

At the same time, unlike SSRIs, azapirones, according to several studies, were ineffective in panic disorder. Although there are data on the possible effectiveness of azapironone in social phobia, it was not possible to prove this in a controlled study. Thus, existing data indicate the efficacy of azapirones only with generalized anxiety disorder. In this case, azapirones favorably differ from benzodiazepines - the main therapeutic agent in this disease - the lack of tolerance and the risk of drug dependence.

Although the point of application of azapirones is known, it remains unclear how this mechanism leads to a therapeutic effect. Azapyrones can act as partial agonists for postsynaptic serotonin 5-HT1A receptors in the hippocampus and prefrontal cortex, as well as for presynaptic autoreceptors on the bodies of serotonergic neurons. Since the effect of azapirones develops within a few days, it seems that it is not related to their direct action on the receptors. Animal studies suggest that the anxiolytic effect of these drugs is related to their effect on presynaptic receptors, and the antidepressant effect is associated with action on postsynaptic receptors.

Azapirones rarely cause side effects. Most importantly, they do not result in tolerance, drug dependence, psychomotor and cognitive side effects, which are characteristic of benzodiazepines, and with withdrawal, withdrawal syndrome. Unlike tricyclic antidepressants, azapirones do not adversely affect the cardiovascular system. Nevertheless, when they are taken, gastrointestinal disturbances, headache, sometimes anxiety, irritability and sleep disturbances are possible. These side effects are rarely so pronounced that they require the drug to be discontinued. There are several reports of the development of extrapyramidal disorders with the administration of azapirones, but they are of a casuistic nature.

Azapirones should be combined with caution with MAO inhibitors due to the risk of increasing blood pressure.

[20], [21], [22], [23], [24],

Tricyclic antidepressants

As with most other drugs that have been used for a long time, the therapeutic effect of tricyclic antidepressants in depression and anxiety disorders has been discovered by chance. The ability of these drugs to reduce depression was seen during clinical trials in psychoses, and their beneficial effect in anxiety disorders was as a result of empirical enumeration of various drugs in an attempt to help such patients (Carlsson, 1987).

The term "tricyclic antidepressants" indicates the general chemical structure of the drugs. All of them consist of two benzene rings, connected by a se-mute ring. Depending on the chemical structure, tricyclic antidepressants are divided into several groups. Thus, one of the groups includes tertiary amines (imipramine, amitriptyline, clomipramine and doxepin), the other is secondary amines (desipramine, nortriptyline, protriptyline and amoxapine). Two secondary amines (desipramine and nortriptyline) are demethylated derivatives of tertiary amines (respectively imipramine and amitriptyline). Since tertiary amines are partially metabolized by demethylation, in patients taking amitriptyline and imipramine, both tertiary and secondary amines circulate in the blood. Tricyclic antidepressants in the past were considered a drug of choice for a variety of anxiety disorders, but at present they are used less often. The decline in their popularity is due not to the fact that they are less effective than new drugs, but rather because they outperform them in safety. Tricyclic antidepressants are still considered a highly effective treatment for various anxiety disorders.

In panic disorder, tricyclic antidepressants are used especially often. The history of their application began with clinical observation - in patients taking tricyclic compounds, regression of panic attacks was noted. Subsequently, a number of researchers noted the effectiveness of these drugs in panic disorder with and without agoraphobia. Initially, imipramine was used primarily for the treatment of panic attacks, but subsequent controlled studies also demonstrated the efficacy of clomipramine, nortriptyline, and other drugs in this group. The study of the effectiveness of serotonin reuptake inhibitors suggests that the therapeutic effect depends on the effect on the serotonergic system, which - from tricyclic antidepressants - is especially pronounced in clomipramine. However, this is probably an oversimplified assumption. SSRIs can indirectly affect the noradrenergic system. Indeed, the fact that desipramine, which primarily affects noradrenergic transmission, is effective in panic disorder, confirms that the therapeutic effect in this condition can be obtained by affecting both the serotonergic and the noradrenergic system.

In initial studies, Klein highlighted the pharmacological differences between a panic disorder reacting to tricyclic antidepressants, but not to benzodiazepines, and a generalized anxiety disorder in which benzodiazepines are effective but not tricyclic antidepressants. However, recently the validity of this conclusion was called into question, since in a controlled trial, the efficacy of tricyclic antidepressants was also demonstrated in the generalized anxiety disorder. Thus, tricyclic antidepressants can be used in the treatment of generalized anxiety disorder, especially if there are concerns about the possibility of developing drug dependence on benzodiazepines.

Although relatively few controlled studies on drug efficacy in PTSD have been conducted, at least four studies have evaluated the efficacy of tricyclic antidepressants in PTSD, but their results are variable. In one study, some efficacy of amitriptyline was noted, in another imipramine was found to be ineffective, in the third it turned out that imipramine is inferior in effectiveness to phenelzine. Due to the lack of convincing clinical studies, it is now impossible to finally determine the role of tricyclic antidepressants in the treatment of PTSD. Because SSRIs are safer and better tolerated and, in addition, there are some data on their effectiveness in PTSD, tricyclic antidepressants recommend that this category of patients be appointed only if SSRIs are ineffective. In addition, tricyclic antidepressants are not considered drugs of choice in the therapy of social phobia, either specific or generalized, since there is convincing evidence of the efficacy of MAO inhibitors and SSRIs in this disease.

The mechanism of action of tricyclic antidepressants is not clear until the end. Most drugs have a direct effect on several neurotransmitter systems, including catecholaminergic, indolaminergic and cholinergic. In preclinical studies, their effect on the reuptake of serotonin and norepinephrine in the brain has been established. Preparations of this group to a different degree block the carriers, carrying out a reverse capture of different neurotransmitters. For example, desipramine has a relatively selective effect on norepinephrine reuptake, and clomipramine on serotonin reuptake; The other representatives have a greater or lesser impact on both types of vectors. As in the case of SSRIs, the direct action of tricyclic antidepressants on neurotransmitter recapture can not fully explain the therapeutic effect of drugs that develops over several days or weeks. The delayed nature of the therapeutic effect suggests that it is associated with slow processes in the brain. It can be assumed that the positive effect of tricyclic antidepressants on anxiety is due to gradual changes in serotonergic and catecholaminergic transmission, changes in the system of the second mediator and changes in the activity of the genetic apparatus.

The use of tricyclic antidepressants limits their side effects. The most significant of them is related to the influence on intracardiac conductivity, which is dose-dependent and leads to changes in the ECG. When using these drugs, tachycardia, an increase in the QT interval, blockage of the bundle of the bundle, changes in the ST interval and the T wave may be possible. According to some data, these changes are more common in children than in adults. Therefore, when appointing tricyclic antidepressants, children need special care. Tricyclic antidepressants can also cause orthostatic hypotension by blocking postsynaptic alpha 1-adrenergic receptors. These side effects complicate the use of tricyclic antidepressants and make them much more dangerous in case of an overdose than SSRIs.

Other side effects of tricyclic antidepressants are not so dangerous, but may be the reason for the patient's refusal to take the drug. These include holinoliticheskie effects: drowsiness, urinary retention, dry mouth, constipation and other gastrointestinal disorders, a violation of accommodation; especially when they occur with the use of tertiary amines. In addition, there may be a violation of cognitive functions associated with blockade of histamine receptors, disorders of sexual function (anorgasmia, delayed ejaculation, decreased libido). Like SSRIs, tricyclic antidepressants can provoke manic episodes - it remains unknown whether all drugs have this property in the same measure. However, there is evidence that the ability to provoke manic episodes is common to all drugs of this class.

The most important contraindications to the appointment of tricyclic antidepressants are heart disease or a serious risk of overdose. Closed-angle glaucoma is less frequent, but no less serious contraindication. Holinolytic action leads to mydriasis, which increases the intraocular pressure in these patients. Although tricyclic antidepressants can be used with open-angle glaucoma, it is advisable to consult a patient with an ophthalmologist. With special care, tricyclic antidepressants should be given to older people, even if they do not have concomitant diseases - they have a high risk of falls caused by orthostatic hypotension. With caution appoint these drugs and children, given the possible cardiotoxic effect, as well as adolescents due to the relatively high risk of overdose in this age group.

When using tricyclic antidepressants, the possibility of drug interaction should be considered. When combined with drugs that inhibit the activity of cytochrome P450 (eg, SSRIs), the concentration of tricyclic antidepressants can reach toxic levels even when low doses are prescribed. Combination with other drugs with holinolitic action may cause delirium and urinary retention. When combined with drugs that have sedative and hypnotic effects (for example, benzodiazepines or antihistamines), oppression of the central nervous system is possible, and in combination with neuroleptics or beta-blockers, cardiotoxicity (even with small doses).

With intoxication with tricyclic antidepressants, the greatest danger is associated with impaired cardiac conduction and the development of life threatening arrhythmia. The difference between therapeutic and toxic doses is quite small (a narrow therapeutic window), and with the use of 1 g, a lethal outcome is possible. This dose is less than the amount of the drug that the patient usually takes in a week. With intoxication, orthostatic hypotension, manifestations of cholinolytic and antihistamine action can also occur. The risk of toxic effect increases with a combination of tricyclic antidepressants with drugs that lower blood pressure, blocking cholinergic transmission and causing sedation.

Monoamine Oxidase Inhibitors

The therapeutic effect of monoamine oxidase inhibitors (MAOI) was discovered accidentally in 1950 in an anti-tuberculosis drug Iproniazide. Since then, MAOI has been successfully used in the treatment of depressive and anxiety disorders. Due to high efficiency, even in patients resistant to the action of other groups of drugs, they are firmly in the arsenal of funds for the treatment of anxiety disorders. Nevertheless, their use is limited, although relatively rare, but potentially fatal side effects.

Monoamine oxidase is one of the main enzymes involved in the metabolic degradation of catecholamines and indolamines. One of the isoforms, MAO-A, contained in the gastrointestinal tract, brain and liver, predominantly metabolizes norepinephrine and serotonin. Another isoform - MAO-B, contained in the brain, liver and platelets (but not in the gastrointestinal tract) - predominantly metabolizes dopamine, phenyl-istilamine and benzylamine. Phenylsin and tranylcypromine are classified as non-selective MAO inhibitors that inhibit the activity of both MAO-A and MAO-B. It is believed that inhibition of MAO-A is important in the therapy of anxiety and depressive disorders, whereas braking of MAO-B is used in the treatment of Parkinson's disease. Selegiline in small doses selectively inhibits the activity of MAO-B, in large doses inhibits both forms of the enzyme. Therefore, it is usually used to treat Parkinson's disease, rather than anxiety or depression. Since these drugs irreversibly bind to MAO, the restoration of enzyme activity after discontinuation of treatment is possible only by the synthesis of its new molecules - this usually takes 1-2 months. The new drug moclobemide is a reversible selective MAO-A inhibitor. Since after drug cancellation there is no need to wait until new enzyme molecules are synthesized, this drug provides a greater degree of freedom when choosing treatment in resistant cases. Although most of the studies have been evaluated for efficacy in anxiety and depressive disorders of "old", nonselective MAOIs, later work is focused on studying the clinical possibilities of new, reversible MAOIs.

MAOI is effective in the treatment of panic disorder, social phobia, PTSD. In a number of cases, MAOIs are particularly effective, for example, in certain types of depression complicated by panic attacks, including atypical depression. In addition, MAOI are effective in social phobia. At least four large studies have shown that they are particularly useful in the generalized form of this disorder.

Since MAO in the brain carries out catabolism of biogenic amines, MAO inhibitors inhibit the metabolism of neurotransmitters-monoamines, increasing their bioavailability and prolonging their action. The relationship between the immediate effect and the therapeutic effect in anxiety disorders remains unclear. As in the case of SSRIs or tricyclic antidepressants, the clinical effect of MAOI manifests itself in a few days or weeks, while the enzyme is already blocked by the first dose of the drug. There are several theories explaining the therapeutic effect of MAOI. Their main essence boils down to the fact that immediate changes in the availability of a neurotransmitter lead to adaptive changes in the expression of genes. In turn, this causes a change in the number or sensitivity of receptors, the state of postreceptor signaling systems.

The most serious side effect when using MAOI is arterial hypertension resulting from the consumption of tyramine-containing foods or beverages ("cheese" reaction). Normally, MAO in the gastrointestinal tract performs metabolic degradation of tyramine, which can provoke an increase in blood pressure, promoting the release of endogenous catecholamines. Tyramine is present in many foods and beverages, including meat, cheese and wine. The admission of tyramine against the background of the MAO blockade provokes a severe hypertensive crisis with signs of sympathetic hyperactivity: fever, tremor, profuse sweating and a possible threat to life. During a crisis, a life-threatening disturbance of the heart rhythm may occur. Patients who take MAOI, when symptoms of hypertensive crisis appear, should be immediately hospitalized in the intensive care unit.

In addition to this rare but dangerous side effect, MAOIs can cause other complications that limit their use, including ortho-static hypotension, agitation, drowsiness, weight gain, suppression of sexual functions. Like other antidepressants, MAOIs can provoke a manic episode in a patient with a corresponding predisposition.

MAOI should be prescribed only to patients who strictly follow the doctor's recommendations for dietary restrictions, which is the key to safe treatment. For example, these drugs are usually not recommended to be prescribed to patients with a pronounced cognitive defect and poorly controlled their behavior. Provoke hypertensive crisis in patients taking MAOI, can not only tiramin-containing products, but also any drugs with sympathomimetic activity. Hazardous consequences can arise as a result of drug interaction of MAOI with narcotic analgesics, oral hypoglycemic agents, levodopa. Like tricyclic antidepressants, MAOI should be administered with caution to elderly patients because of the risk of orthostatic hypotension.

MAOIs are extremely toxic in overdose, and the symptoms of intoxication do not necessarily appear immediately. These include epileptic seizures, heart rhythm disturbances, rhabdomyolysis and coagulopathy.

Benzodiazepines

The appearance of benzodiazepines in the 1960s revolutionized psychopharmacology. By its name, this class of drugs is due to a chemical structure common to all, including a benzene ring, connected by a semi-diazepine ring. The individual pharmacological properties of benzodiazepines depend on the substitutions in the rings. Before the advent of benzodiazepines, barbiturates were most commonly used as sedatives and hypnotics. But benzodiazepines quickly replaced barbiturates, since the latter could cause severe respiratory depression, and after prolonged use, a dangerous withdrawal syndrome. Since benzodiazepines are safer, currently barbiturates are rarely involved in the daily practice of treating anxiety and insomnia.

Doctors most often prescribe benzodiazepines to obtain an anxiolytic effect, which is detected at relatively low doses, and also as a hypnotic. Due to the strength of the anxiolytic effect, benzodiazepines are often divided into high-potential (clonazepam and alprazolam) and low-potential (chlordiazepoxide, diazepam and most other drugs for oral administration). The strength indicators of the anxiolytic effect should not be confused with the parameters of drug distribution or the half-eli- mination period. The strength of the drug is determined by the dose necessary to obtain a certain effect; the half-elimination period characterizes the time necessary for the metabolism and elimination of the drug. The half-distribution period is determined by the time necessary for distribution in lipid-rich tissues, such as the brain, and the half-elimination period is the time required for metabolism. It should be noted that many benzodiazepines form clinically active metabolites. Typically, high-potential benzodiazepines are characterized by a relatively short half-distribution and semi-elimination period, although this feature is also characteristic of some low-potential benzodiazepines. The strength of drugs is of great clinical importance. For example, in the treatment of panic disorder, high-potential benzodiazepines are most often used. From the half-elimination period, the likelihood of developing tolerance, dependence and withdrawal syndrome depends: when taking drugs with a faster distribution and elimination, drug dependence is more likely.

A number of randomized controlled clinical trials have shown the efficacy of low-potential benzodiazepines in generalized anxiety disorders. However, many of these publications are difficult to interpret, since they were made before the introduction of DSM-IV. Since the definition of a generalized anxiety disorder has undergone important changes, it is unclear to what extent the results of earlier clinical studies are applicable to that state whose boundaries are outlined by modern criteria. Nevertheless, benzodiazepines are considered effective in generalized anxiety disorder, regardless of the criteria on which it is diagnosed. As for the treatment of panic disorder, the most complete data are available on the use of two high-potential benzodiazepines of alprazolam and clonazepam. Three controlled clinical trials of high-potential benzodiazepines in social phobia have been carried out. In one of them, clonazepam had an advantage over placebo, in others it was not possible to prove effectiveness, including because of methodological flaws that prevented a definite conclusion. In a controlled trial of alprazolam with PTSD, the effectiveness of the drug was not proven.

Gamma-aminobutyric acid (GABA) is the most important inhibitory mediator in the brain. There are at least two classes of receptors: GABA and GABQB. Benzodiazepines act only on GABA-receptors. The GABA-receptor is a macromolecular complex that includes a binding site for benzodiazepines (a benzodiazepine receptor) and a ligand-dependent chlorine channel. The combination of GABA with the receptor leads to the opening of the channel, and chlorine ions rush into the cell, which leads to its hyperpolarization and an increase in the threshold of cellular excitation. Many substances, including barbiturates, alcohol, benzodiazepines, are active through the activation of GABA-receptors. Benzodiazepines and other drugs act on different sites of the GABA complex. Therefore, with the simultaneous intake, for example, of alcohol and benzodiazepines, their effect is summarized, which can lead to death. Unlike tetricyclic antidepressants and SSRIs, the therapeutic effect of benzodiazepines appears after the first dose. Consequently, it is the interaction of benzodiazepines with GABA receptors that determines the clinical effect. Since benzodiazepine receptors are located throughout the brain, special neuronal systems providing an anxiolytic effect could not be detected. Recent studies show that the development of conditioned-reflex fear is provided by limbic structures, including the septo-hypokampal complex and the amygdala.

Unlike tricyclic antidepressants and MAO inhibitors, benzodiazepines do not have any serious effect on the cardiovascular system, which makes them indispensable for a wide range of somatic diseases accompanied by anxiety. Although benzodiazepines in moderate doses can cause respiratory depression, this effect is less dramatic than other sedatives and hypnotics. The most common side effects of benzodiazepines are associated with a depressant effect on the central nervous system. These include rapid fatigue, drowsiness, impaired concentration, especially when taking high doses. Benzodiazepines also worsen cognitive functions (including memory, learning ability) and can cause ataxia. Although benzodiazepines can increase depression, high-potential members of this group are able to reduce the severity of depressive symptoms. In children and patients with organic brain lesions, benzodiazepines can cause disinhibition, characterized by outbursts of rage, excitement, impulsivity. But the main limiting factor in the use of benzodiazepines appears to be the risk of physical dependence and withdrawal syndrome. Like other drugs that depress the central nervous system, benzodiazepines can cause addiction.

It should avoid the appointment of benzodiazepines to patients who have a history of drug addiction or drug dependence. If the need for them does arise, then in this category of patients they should be used with extreme caution. Organic brain damage with cognitive impairment is also a relative contraindication to the appointment of benzodiazepines, since they can cause disinhibited behavior and aggravate the cognitive defect. Since patients with impaired liver function, active metabolites of benzodiazepines can accumulate, these drugs should be used with caution in the elderly, even if they do not have cognitive impairment. Similar precautions should be observed for persons suffering from pulmonary diseases - take into account the ability of benzodiazepines to depress respiration. It is dangerous to combine benzodiazepines with other drugs that depress the central nervous system, such as alcohol or barbiturates, which can lead to severe respiratory depression with a fatal outcome, even if each of these drugs is administered in a small dose.

Compared with tricyclic antidepressants and MAO inhibitors, benzodiazepines are relatively safe in overdose (if taken without other drugs), but when combined with other CNS depressants, life-threatening risks may occur.

[25], [26], [27], [28], [29], [30],

Other drugs

The drugs described above are the main means of treatment for anxiety disorders, but other means are sometimes used in these conditions.

Beta-blockers

Although beta-adrenoblockers are used for various mental disorders, their effectiveness under such conditions is not proven. Preparations of this group are ineffective both in panic and generalized anxiety disorders. Of particular interest are data on the use of beta-blockers in PTSD, but in this case there is no convincing evidence to confirm their effectiveness. Perhaps the only established indication for beta-blockers is performance anxiety, which occurs, for example, during an exam or public appearance and is a specific form of social phobia. The main advantage of these drugs over benzodiazepines is the minimal effect on cognitive functions. When "anxiety performance" beta-blockers are assigned once, but if necessary, repeated reception is possible. The most commonly used propranolol in a dose of 10 to 40 mg - it should be taken an hour before the speech. It should be noted that these drugs are ineffective in the generalized form of social phobia.

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

Alpha-altrenergic receptor agonists

According to one theory, the hyperactivity of the blue spot neurons plays an important role in the pathogenesis of panic disorder and related anxiety conditions. Since the alpha 2-adrenoreceptor agonist clonidine reduces the excitability of the neurons of the blue spot, it can be effective in these disorders. This assumption was confirmed in the study of withdrawal symptoms in addicts, which is accompanied by anxiety and increased activity of neurons of the blue spot. It turned out that clonidine in this state has a positive effect and can be used as an auxiliary. Controlled clinical trials suggest that clonidine may have a moderate effect in panic disorder, but side effects limit its use.

[39], [40], [41], [42], [43], [44], [45], [46]

Anticonvulsants

There is growing interest in the use of anticonvulsants in various mental illnesses. The effect of carbamazepine and valproic acid on bipolar disorder was best studied. The use of anticonvulsants in patients with bipolar disorder was prompted by experimental data. The study of the laboratory model of epilepsy in animals revealed neurobiological phenomena characteristic of bipolar disorder. Preliminary data indicate that valproic acid may be effective in panic disorder, but this result should be confirmed in randomized clinical trials. There are also data on the successful use of valproic acid in PTSD. At present, valproic acid is considered a third-line drug in the treatment of anxiety disorders. It is indicated in case of ineffectiveness of other agents in the presence of possible signs of bipolar disorder.

Other antidepressants that affect serotonergic norepinephrine transmission. Trazodone is an antidepressant that activates the serotonergic system, possibly through its meta-chlorophenylpiperazine metabolite. Although trazodone is not a first-line drug in most anxiety disorders, a randomized clinical trial shows its effectiveness in generalized anxiety disorder. Trazodone has no significant effect on cardiac conduction, but can cause orthostatic hypotension. Priapism is a rare but significant side effect of the drug.

At present, a number of new drugs have appeared that have some properties of traditional drugs used in the therapy of anxiety disorders. These include venlafaxine, which blocks the re-uptake of both serotonin and norepinephrine. It can be effective in panic disorder, but the experience of its use is small. Nefazodone, structurally close to trazodone and, like it, metabolized with the formation of chlorophenylpiperazine, can also have a positive effect in some anxiety disorders. Preliminary data show that ritanserin, a 5-HT 2 receptor antagonist, is not effective in anxiety disorders. Of the other serotonergic drugs that can have a positive effect in anxiety disorders, Odansetron, an antagonist of 5-HT3 receptors, should be mentioned. According to preliminary data, it is effective in generalized anxiety disorder.

[47], [48], [49], [50]

Experimental methods of treatment

Fundamental studies of panic disorder allow us to look for new ways to treat this condition and other anxiety disorders. Based on the hypothesis about the possible role of calcium-dependent mechanisms in the system of the second mediator in mental disorders, the researchers examined the efficacy of inositol in panic disorder, obsessive-compulsive disorder and major depression. Although one of the small, controlled clinical trials had positive results in the treatment of panic disorder, this therapy is still considered experimental. Based on data on the relationship between hyperventilation and cerebral blood flow in panic disorder, a study was undertaken of calcium antagonists, which showed some positive effect. Given that the infusion of cholecystokinin is capable of provoking panic attacks in persons with a predisposition to them, antagonists of cholecystokinin receptors are currently being developed as potential antipanic and anxiolytic agents.

[51], [52]