Anxiety disorders

It is now generally accepted that anxiety disorders are a group of closely related, yet distinct, psychopathological conditions. This is reflected in the relatively minor changes in the basic categorization of anxiety disorders that were made in the fourth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM) compared with the third revision of DSM. According to DSM-W, nine conditions are classified as primary "anxiety disorders": panic disorder with and without agoraphobia; agoraphobia without panic disorder; specific phobias; social phobia; obsessive-compulsive disorder; posttraumatic stress disorder; acute stress disorder; and generalized anxiety disorder.

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Causes anxiety disorders

The causes of anxiety disorders are not entirely known, and both mental and physical factors are involved. Many people develop anxiety disorders without any clear triggers. Anxiety may be a response to external stressors, such as the end of a significant relationship or the presence of a life-threatening danger. Some physical illnesses themselves cause anxiety, such as hyperthyroidism, pheochromocytoma, hyperadrenocorticism, heart failure, arrhythmias, asthma, and chronic obstructive pulmonary disease (COPD). Other physical causes include medication use; the effects of glucocorticoids, cocaine, amphetamines, and even caffeine can mimic anxiety disorders. Withdrawal from alcohol, sedatives, and some illicit drugs can also cause anxiety.

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Pathogenesis

Everyone experiences fear and anxiety from time to time. Fear is an emotional, somatic, and behavioral response to an immediately recognizable external threat (such as an attack or the possibility of a car accident). Anxiety is an unpleasant emotional state of nervousness and worry; its causes are not as obvious as those of fear.

Anxiety is less temporally related to threat; it may anticipate the threat, persist after the danger has passed, or occur in the absence of a specific threat. Anxiety is often accompanied by somatic changes and behavior similar to fear.

A certain level of anxiety is adaptive, it allows one to prepare and improve the level of functioning of the body, which allows a person to be more careful in potentially dangerous situations. However, when anxiety exceeds a certain level, it causes dysfunction and severe distress. In this situation, anxiety is maladaptive and is considered a disorder.

Anxiety occurs in various mental and somatic illnesses, but in some of them it is the dominant symptom. Anxiety disorders are more common than other types of mental pathology. However, sometimes they are not recognized and, as a result, are not treated. Chronic maladaptive anxiety that remains untreated can aggravate or hinder the treatment of a number of somatic illnesses.

In medical literature, the term "anxiety" is understood as fear or apprehension that is excessive in relation to a specific life situation. Thus, an extreme degree of fear or apprehension is defined as "pathological anxiety" if they are inadequate to the level of human development - for example, the fear of leaving home in a high school student, or to personal life circumstances - for example, the fear of losing a job in a person who successfully copes with it. Clinical research over the past 30 years has been accompanied by a constant improvement in the understanding 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 in the circle of other mental disorders was determined more clearly, partly under the influence of pharmacological research.

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Symptoms anxiety disorders

Anxiety can arise suddenly, like panic, or build gradually over minutes, hours, or even days. Anxiety can last from a few seconds to years, with longer durations more common in anxiety disorders. Anxiety ranges from barely noticeable unease to panic.

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

The decision whether anxiety is so prevalent and severe that it constitutes a disorder is determined by a number of factors. The physician evaluates the extent to which these factors determine the diagnosis. The physician first needs to determine, based on the patient's history, physical examination, and appropriate laboratory tests, whether the anxiety is the result of a medical condition or substance use disorder. It is also necessary to determine whether the anxiety is a symptom of another mental disorder. If no other cause for the anxiety is found, if the anxiety causes significant distress and disrupts functioning, and if it does not resolve spontaneously within a few days, then an anxiety disorder is likely and requires treatment.

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Diagnostics anxiety disorders

The diagnosis of a specific anxiety disorder is based on characteristic symptoms and signs. 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 their relatives, as well as a general predisposition to develop anxiety disorders. However, some patients may exhibit the same disorders as their relatives through the mechanism of behavioral pattern adoption.

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Treatment anxiety disorders

The importance of diagnosing comorbid conditions should be emphasized. For example, patients with anxiety disorder often have depression, and only if it is recognized and corrected will treatment be successful. In addition, anxiety disorders are often complicated by the development of dependence on psychotropic drugs, which requires a special approach to treatment. Another example: in uncomplicated generalized anxiety disorder, benzodiazepines may be the drug of choice, but they are ineffective if generalized anxiety disorder is combined with major depression, and are inappropriate for patients who abuse psychotropic substances.

Selection of treatment for anxiety disorders also requires consideration of the patient's somatic status. All patients with newly developed anxiety should undergo a thorough physical examination to detect signs of somatic or neurological diseases that can cause symptoms of anxiety disorders. A thorough history of current and past medications is also important for the selection of therapy. If abuse of psychotropic drugs is suspected, laboratory testing is necessary. A consultation with a neurologist is usually not necessary, but if symptoms of a neurological disease are detected, a thorough neurological examination is necessary.

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors are a unique class of drugs. Before their development in the 1980s, the search for new drugs to treat anxiety, like most other mental disorders, was empirical, based on random clinical observations. Psychotropic drugs developed before SSRIs acted on many neurotransmitter systems. In contrast, SSRIs were designed to selectively act only on the presynaptic serotonin reuptake site at the terminals of serotonergic neurons. This choice was predetermined by observations that drugs effective in treating anxiety and depression had one common property: they inhibited serotonin reuptake in the brain.

The effectiveness of SSRIs in the treatment of anxiety and depression has pointed to the important role of serotonin in the pathogenesis of these conditions. This has led to the creation of new models of mental disorders in laboratory animals and has given a new direction to genetic research in humans. The effectiveness of SSRIs in a wide range of mental disorders has also stimulated the search for similarities and differences in the neurochemical basis of anxiety and depressive disorders. In clinical practice, SSRIs have become widely popular because they combine high effectiveness in a number of mental disorders with good tolerability and safety.

There are five drugs currently in use that are SSRIs: fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. A sixth drug, zimelidine, has been withdrawn because several cases of Guillain-Barré syndrome have been reported with its use. This chapter provides a general description of all five drugs as a single group, highlighting individual differences between the drugs only when they are clinically significant.

Several large randomized controlled clinical trials have demonstrated the efficacy of SSRIs in the treatment of acute episodes of various types of anxiety disorders. Apart from obsessive-compulsive disorder, the greatest experience with SSRIs has been accumulated in panic disorder. Fluvoxamine, paroxetine, sertraline, and citalopram have been shown to be effective in this condition. Although there is virtually 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 drugs mainly concern the duration of the half-elimination period and the ability to interact with other drugs. The latter feature mainly depends on differences in the effect on liver enzymes that metabolize drugs.

There are only a few publications on the efficacy of SSRIs in anxiety disorders other than panic disorder. Two of three small studies showed the efficacy of fluvoxamine and sertraline in social phobia, while the study of paroxetine was less definitive. One study showed the efficacy of fluoxetine in PTSD, and it was effective in the effects of civilian trauma, but not in war veterans. There are no publications on the efficacy of SSRIs in isolated generalized anxiety disorder. Although there is evidence for the efficacy of most SSRIs in panic disorder, only paroxetine is FDA-approved for this indication.

SSRIs have also been shown to be effective in the treatment of major depression and dysthymia, which are often associated 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 in which group of anxious patients SSRIs are more effective: in patients with or without comorbid depression. SSRIs are known to be able to prevent relapse of major depression, but few studies have examined this property in relation to anxiety disorders. Nevertheless, SSRIs are prescribed to prevent relapse of anxiety disorders for months or years in cases where they have been effective in treating acute episodes.

There are few direct comparative studies of the effectiveness of SSRIs and other drugs effective in anxiety disorders. Clinicians often prefer SSRIs to tricyclic antidepressants, MAO inhibitors, and benzodiazepines because they have a more favorable side effect profile, are less likely to cause drug dependence, and do not pose a serious risk of overdose.

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

It is generally accepted that serotonin reuptake blockade underlies the therapeutic action 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 cannot be explained directly by the reuptake blockade, which develops immediately. It is assumed that with long-term use of the drug, the influence of serotonergic neurons of the raphe nuclei on the prefrontal cortex and limbic structures increases. But how this correlates with the reduction of anxiety and depressive disorders in humans remains unknown.

The main advantage of SSRIs over other drugs is a more favorable side effect profile. It is especially important that SSRIs have a minimal effect on the cardiovascular system. In contrast, tricyclic antidepressants can cause cardiac conduction disorders and a drop in blood pressure. The most common side effects of SSRIs include irritability and anxiety, which can disrupt sleep (especially if treatment is started with high doses), as well as headache. Gastrointestinal disorders are also common: nausea, constipation, diarrhea, anorexia. One of the most unpleasant aspects of SSRI use is that they often cause sexual dysfunction in both sexes, in particular, decreased libido and anorgasmia. Rarer side effects include urinary retention, sweating, visual disturbances, akathisia, dizziness, increased fatigue, movement disorders. Like other antidepressants, SSRIs can provoke mania. Since direct comparative studies of the risk of developing mania with the use of antidepressants of different classes have been practically not conducted, it remains unclear whether SSRIs are safer in this regard or not.

There are virtually no absolute contraindications to the use of SSRIs. However, they should be combined with caution with other drugs. SSRIs inhibit the activity of various cytochrome P450 isoenzymes, a family of liver enzymes that metabolize many drugs. As a result, the concentration of some drugs in the blood, if prescribed together with SSRIs, can reach toxic levels. For example, this occurs when combining tricyclic antidepressants with fluoxetine or sertraline, theophylline or haloperidol with fluvoxamine, phenytoin with fluoxetine. However, SSRIs can be combined with a tricyclic antidepressant, but only under the condition of 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 prescribing SSRIs, you should check the relevant publications about the possibility of their interaction with other drugs that the patient is taking.

SSRIs do not cause serious complications, even if their dose is five or ten times higher than the therapeutic dose. Although in adults, agitation, vomiting, and occasionally epileptic seizures are possible, no fatal outcome has been recorded with an overdose of only one SSRI. At the same time, two fatal outcomes have been described following the use of high doses of fluoxetine (at least 1800 mg) in combination with other drugs.

Azapirones

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

Buspirone is licensed for the treatment of generalized anxiety disorder. As with SSRIs, the effect of buspirone in generalized anxiety disorder occurs only after several days of continuous use. Buspirone is as effective as benzodiazepines in this disorder, although it does not act as quickly as they do (Rickels et al., 1988). A randomized clinical trial demonstrated the effectiveness of buspirone in major depression, especially when accompanied by severe anxiety; however, the validity of these results has been questioned due to the large number of study dropouts. A randomized trial also showed that buspirone reduces anxiety in alcoholics with comorbid generalized anxiety disorder after detoxification.

At the same time, unlike SSRIs, azapirones have been shown to be ineffective in panic disorder according to several studies. Although there is evidence that azapirones may be effective in social phobia, this has not been proven in a controlled study. Thus, existing data indicate that azapirones are effective only in generalized anxiety disorder. At the same time, azapirones compare favorably with benzodiazepines, the main therapeutic agent for this disorder, in the absence of tolerance and the risk of developing drug dependence.

Although the site of action of azapirones is known, how this mechanism results in the therapeutic effect remains unclear. Azapirones may act as partial agonists at postsynaptic serotonin 5-HT1A receptors in the hippocampus and prefrontal cortex, as well as at presynaptic autoreceptors on the cell bodies of serotonergic neurons. Because the effect of azapirones develops over several days, it does not appear to be due to a direct action on receptors. Animal studies suggest that the anxiolytic effect of these drugs is due to their action at presynaptic receptors, and the antidepressant effect is due to their action at postsynaptic receptors.

Azapirones rarely cause side effects. What is especially important is that their use does not cause tolerance, drug dependence, psychomotor and cognitive side effects typical of benzodiazepines, and withdrawal syndrome does not occur upon discontinuation of use. Unlike tricyclic antidepressants, azapirones do not have an adverse effect on the cardiovascular system. However, gastrointestinal disturbances, headache, sometimes anxiety, irritability and sleep disturbances are possible when taking them. These side effects are rarely so pronounced that they require discontinuation of the drug. There are several reports of extrapyramidal disorders developing when taking azapirones, but they are casuistic in nature.

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

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Tricyclic antidepressants

As with most other drugs in long-term use, the therapeutic effects of tricyclic antidepressants in depression and anxiety disorders were discovered by chance. The ability of these drugs to reduce depression was noted in clinical trials in psychosis, and their beneficial effects in anxiety disorders were the result of an empirical trial of various drugs in an attempt to help such patients (Carlsson, 1987).

The term "tricyclic antidepressants" refers to the general chemical structure of the drugs. They all consist of two benzene rings connected by a seven-membered 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), another - secondary amines (desipramine, nortriptyline, protriptyline and amoxapine). Two secondary amines (desipramine and nortriptyline) are demethylated derivatives of tertiary amines (imipramine and amitriptyline, respectively). Since tertiary amines are partially metabolized by demethylation, both tertiary and secondary amines circulate in the blood of patients taking amitriptyline and imipramine. Tricyclic antidepressants were once considered the drug of choice for a variety of anxiety disorders, but are now used less frequently. Their decline in popularity is not because they are less effective than newer drugs, but rather because the newer drugs are safer. Tricyclic antidepressants are still considered highly effective in treating a variety of anxiety disorders.

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

In Klein's initial studies, he emphasized the pharmacological differences between panic disorder, which responds to tricyclic antidepressants but not to benzodiazepines, and generalized anxiety disorder, which responds to benzodiazepines but not tricyclic antidepressants. However, this conclusion has recently been questioned because a controlled study has demonstrated the efficacy of tricyclic antidepressants in generalized anxiety disorder as well. Thus, tricyclic antidepressants may also be useful in the treatment of generalized anxiety disorder, especially when there is concern about the potential for drug dependence on benzodiazepines.

Although relatively few controlled trials of drug efficacy in PTSD have been conducted, at least four studies have evaluated the efficacy of tricyclic antidepressants in PTSD, but the results are variable. One study found some efficacy of amitriptyline, another found imipramine ineffective, and a third found imipramine inferior to phenelzine. In the absence of conclusive clinical trials, it is currently impossible to definitively determine the role of tricyclic antidepressants in the treatment of PTSD. Because SSRIs are safer and better tolerated, and because there is some evidence of their efficacy in PTSD, tricyclic antidepressants are recommended for this category of patients only if SSRIs have failed. In addition, tricyclic antidepressants are not considered the drugs of choice for the treatment of social phobia, either specific or generalized, because there is strong evidence of the efficacy of MAO inhibitors and SSRIs in this disorder.

The mechanism of action of tricyclic antidepressants is not fully understood. Most drugs have a direct effect on several neurotransmitter systems, including catecholaminergic, indolaminergic, and cholinergic. Preclinical studies have shown that they affect the reuptake of serotonin and norepinephrine in the brain. Drugs in this group block the transporters that reuptake different neurotransmitters to varying degrees. For example, desipramine is relatively selective in the reuptake of norepinephrine, and clomipramine is selective in the reuptake of serotonin; other drugs affect both types of transporters to a greater or lesser extent. As with SSRIs, the direct effect of tricyclic antidepressants on the reuptake of neurotransmitters cannot fully explain the therapeutic effect of the drugs, which 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 explained by gradual changes in serotonergic and catecholaminergic transmission, changes in the second messenger system and changes in the activity of the genetic apparatus.

The use of tricyclic antidepressants is limited by their side effects. The most significant of these is associated with the effect on intracardiac conduction, which is dose-dependent and leads to changes in the ECG. When using these drugs, tachycardia, an increase in the QT interval, bundle branch block, changes in the ST interval and T wave are possible. According to some data, these changes are more common in children than in adults. Therefore, special caution is needed when prescribing tricyclic antidepressants to children. Tricyclic antidepressants can also cause orthostatic hypotension by blocking postsynaptic alpha1-adrenergic receptors. These side effects complicate the use of tricyclic antidepressants and make them much more dangerous in case of overdose than SSRIs.

Other side effects of tricyclic antidepressants are not as dangerous, but may be the reason for the patient to refuse to take the drug. These include anticholinergic effects: drowsiness, urinary retention, dry mouth, constipation and other gastrointestinal disorders, accommodation disorder; they occur especially often when taking tertiary amines. In addition, cognitive impairment associated with the blockade of histamine receptors, sexual dysfunction (anorgasmia, delayed ejaculation, decreased libido) may occur. Like SSRIs, tricyclic antidepressants can provoke manic episodes - it remains unknown whether all drugs have this property to the same extent. However, there is evidence that the ability to provoke manic episodes is characteristic of all drugs in this class.

The most important contraindications to the use of tricyclic antidepressants are heart disease or a serious risk of overdose. Closed-angle glaucoma is a less common but no less serious contraindication. The anticholinergic effect leads to mydriasis, which contributes to an increase in intraocular pressure in these patients. Although tricyclic antidepressants can be used in open-angle glaucoma, it is recommended to consult an ophthalmologist beforehand. Tricyclic antidepressants should be prescribed with particular caution to elderly people, even if they have no concomitant diseases - they have a high risk of falls caused by orthostatic hypotension. These drugs are also prescribed with caution to children, given the possible cardiotoxic effect, and to adolescents due to the relatively high risk of overdose in this age group.

When using tricyclic antidepressants, the possibility of drug interactions should be taken into account. When combined with drugs that inhibit cytochrome P450 activity (e.g., SSRIs), the concentration of tricyclic antidepressants may reach toxic levels even when low doses are prescribed. Combination with other drugs that have an anticholinergic effect may cause delirium and urinary retention. When combined with drugs that have a sedative and hypnotic effect (e.g., benzodiazepines or antihistamines), CNS depression is possible, and when combined with neuroleptics or beta-blockers, a cardiotoxic effect (even when using low doses) is possible.

In case of intoxication with tricyclic antidepressants, the greatest danger is associated with cardiac conduction disturbances and the development of life-threatening arrhythmia. The difference between the therapeutic and toxic doses is quite small (narrow therapeutic window), and a lethal outcome is possible when taking 1 g. This dose is less than the amount of the drug that a patient usually takes per week. Intoxication may also cause orthostatic hypotension, manifestations of cholinolytic and antihistamine effects. The risk of a toxic effect increases when tricyclic antidepressants are combined with drugs that lower blood pressure, block cholinergic transmission and cause a sedative effect.

Monoamine oxidase inhibitors

The therapeutic effect of monoamine oxidase inhibitors (MAOIs) was discovered accidentally in 1950 in the anti-tuberculosis drug iproniazid. Since then, MAOIs have been successfully used in the treatment of depressive and anxiety disorders. Due to their high efficiency, even in patients resistant to other groups of drugs, they have firmly entered the arsenal of drugs for the treatment of anxiety disorders. However, their use is limited by 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, is found in the gastrointestinal tract, brain, and liver and primarily metabolizes norepinephrine and serotonin. Another isoform, MAO-B, is found in the brain, liver, and platelets (but not in the gastrointestinal tract) and primarily metabolizes dopamine, phenylethylamine, and benzylamine. Phenelzine and tranylcypromine are nonselective MAO inhibitors that inhibit the activity of both MAO-A and MAO-B. Inhibition of MAO-A is believed to be important in the treatment of anxiety and depressive disorders, while inhibition of MAO-B is used in the treatment of Parkinson's disease. Selegiline in small doses selectively inhibits MAO-B activity, and in large doses inhibits both forms of the enzyme. Therefore, it is usually used to treat Parkinson's disease, but not anxiety or depression. Since these drugs irreversibly bind to MAO, enzyme activity can only be restored after treatment is stopped by synthesizing new molecules - this usually takes 1-2 months. The new drug moclobemide is a reversible, selective MAO-A inhibitor. Since there is no need to wait for new enzyme molecules to be synthesized after drug withdrawal, this drug provides a greater degree of freedom in choosing treatment in resistant cases. Although most studies have been devoted to assessing the efficacy of "old", non-selective MAOIs in anxiety and depressive disorders, more recent work has focused on studying the clinical capabilities of new, reversible MAOIs.

MAOIs are effective in treating panic disorder, social phobia, and PTSD. In some cases, MAOIs are particularly effective, for example, in certain types of depression complicated by panic attacks, including atypical depression. In addition, MAOIs are effective in treating 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 catabolizes biogenic amines, MAO inhibitors inhibit the metabolism of monoamine neurotransmitters, increasing their bioavailability and prolonging their action. The relationship between the immediate effect and the therapeutic effect in anxiety disorders remains unclear. As with SSRIs or tricyclic antidepressants, the clinical effect of MAOIs occurs after several days or weeks, while the enzyme is blocked by the first dose of the drug. There are several theories explaining the therapeutic effect of MAOIs. Their main essence is that immediate changes in neurotransmitter availability lead to adaptive changes in gene expression. In turn, this causes a change in the number or sensitivity of receptors, the state of post-receptor signaling systems.

The most serious side effect of MAOIs is hypertension resulting from the consumption of tyramine-containing foods or drinks (the "cheese" reaction). Normally, MAOIs in the gastrointestinal tract carry out 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 drinks, including meat, cheese, and wine. The intake of tyramine against the background of MAO blockade provokes a severe hypertensive crisis with signs of sympathetic hyperactivity: fever, tremors, profuse sweating, and a possible threat to life. Life-threatening cardiac arrhythmia may occur during the crisis. Patients taking MAOIs should be immediately hospitalized in the intensive care unit if signs of a hypertensive crisis appear.

In addition to this rare but dangerous side effect, MAOIs can cause other complications that limit their use, including orthostatic hypotension, agitation, drowsiness, weight gain, and sexual dysfunction. Like other antidepressants, MAOIs can trigger a manic episode in a patient with a predisposition to it.

MAOIs should be prescribed only to those patients who will strictly follow the doctor's recommendations regarding dietary restrictions, which is the key to the safety of treatment. For example, these drugs are usually not recommended for patients with severe cognitive impairment and poor behavioral control. Hypertensive crisis in patients taking MAOIs can be provoked not only by tyramine-containing products, but also by any drugs with sympathomimetic activity. Dangerous consequences can arise as a result of drug interactions of MAOIs with narcotic analgesics, oral hypoglycemic agents, levodopa. Like tricyclic antidepressants, MAOIs should be prescribed with caution to elderly patients due to the risk of orthostatic hypotension.

MAOIs are extremely toxic in overdose, and symptoms of toxicity are not necessarily immediate. These include seizures, cardiac arrhythmia, rhabdomyolysis, and coagulopathy.

Benzodiazepines

The emergence of benzodiazepines in the 1960s revolutionized psychopharmacology. This class of drugs owes its name to their common chemical structure, which includes a benzene ring linked to a seven-membered diazepine ring. The individual pharmacological properties of benzodiazepines depend on the substitutions in the rings. Before the emergence of benzodiazepines, barbiturates were most often used as sedatives and hypnotics. However, benzodiazepines quickly replaced barbiturates, since the latter could cause severe respiratory depression and, after prolonged use, a dangerous withdrawal syndrome. Since benzodiazepines are safer, barbiturates are now rarely used in the routine treatment of anxiety and insomnia.

Physicians most often prescribe benzodiazepines for their anxiolytic effect, which occurs at relatively low doses, and as hypnotics. Benzodiazepines are often classified by their anxiolytic potency as high-potency (clonazepam and alprazolam) or low-potency (chlordiazepoxide, diazepam, and most other oral agents). Potency of anxiolytic effect should not be confused with drug distribution or half-life. Drug potency is determined by the dose required to produce a given effect; half-life is the time required for the drug to be metabolized and eliminated. Distribution half-life is the time required for distribution into lipid-rich tissues such as the brain, and elimination half-life is the time required for metabolism. It should be noted that many benzodiazepines form clinically active metabolites. High-potency benzodiazepines typically have relatively short half-lives, although some low-potency benzodiazepines also have this feature. The potency of the drugs has important clinical implications. For example, high-potency benzodiazepines are most often used to treat panic disorder. The half-lives determine the likelihood of developing tolerance, dependence, and withdrawal syndrome: drugs with faster distribution and elimination are more likely to develop drug dependence.

A number of randomized controlled trials have demonstrated the efficacy of low-potency benzodiazepines in generalized anxiety disorder. However, many of these publications are difficult to interpret because they predate the introduction of DSM-IV. Because the definition of generalized anxiety disorder has undergone important changes, it is unclear to what extent the results of earlier trials apply to the condition as defined by current criteria. Nevertheless, benzodiazepines are considered effective in generalized anxiety disorder, regardless of the criteria by which it is diagnosed. For the treatment of panic disorder, the most comprehensive data are available for the two high-potency benzodiazepines, alprazolam and clonazepam. Three controlled trials of high-potency benzodiazepines have been conducted in social phobia. In one of them, clonazepam had an advantage over placebo, in others, the effectiveness could not be demonstrated, including due to methodological flaws that prevented reaching a definitive conclusion. In a controlled study of alprazolam in PTSD, the effectiveness of the drug could not be demonstrated.

Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the brain. There are at least two classes of receptors: GABA and GABA. Benzodiazepines act only on GABA receptors. The GABA receptor is a macromolecular complex that includes a benzodiazepine binding site (benzodiazepine receptor) and a ligand-dependent chloride channel. The binding of GABA to the receptor leads to the opening of the channel, and chloride ions rush into the cell, which leads to its hyperpolarization and an increase in the threshold of cellular excitation. Many substances act through the activation of GABA receptors, including barbiturates, alcohol, and benzodiazepines. Benzodiazepines and other drugs act on different parts of the GABA complex. Therefore, when taking, for example, alcohol and benzodiazepines at the same time, their effect is summarized, which can lead to a lethal outcome. Unlike tricyclic antidepressants and SSRIs, the therapeutic effect of benzodiazepines occurs after the first dose. Therefore, it is the interaction of benzodiazepines with GABA receptors that determines the clinical effect. Since benzodiazepine receptors are located throughout the brain, it has not been possible to identify specific neuronal systems that provide anxiolytic effects. Recent studies indicate that the development of conditioned reflex fear is provided by limbic structures, including the septo-hippocampal 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 medium doses can cause respiratory depression, this effect is not as dramatic as that of 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-potency representatives of this group are able to reduce the severity of depressive symptoms. In children and patients with organic brain damage, benzodiazepines can cause disinhibition, characterized by outbursts of rage, agitation, and impulsivity. But the main limitation of benzodiazepine use appears to be the risk of physical dependence and withdrawal syndrome. Like other drugs that depress the central nervous system, benzodiazepines can cause dependence.

Benzodiazepines should be avoided in patients with a history of drug abuse or dependence. If they are needed, they should be used with extreme caution in this category of patients. Organic brain damage with cognitive impairment is also a relative contraindication to benzodiazepines, as they may cause disinhibited behavior and worsen cognitive impairment. Since active metabolites of benzodiazepines may accumulate in patients with impaired liver function, these drugs should be used with caution in the elderly, even if they do not have cognitive impairment. Similar precautions should be taken in patients with pulmonary diseases, taking into account the ability of benzodiazepines to depress respiration. It is dangerous to combine benzodiazepines with other CNS depressants such as alcohol or barbiturates, as this can lead to severe respiratory depression with fatal outcome, even if each of these agents is administered in small doses.

Compared with tricyclic antidepressants and MAO inhibitors, benzodiazepines are relatively safe in overdose (when taken alone), but when combined with other CNS depressants, they can be life-threatening.

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

Other drugs

The medications described above are the mainstays of treatment for anxiety disorders, but other medications are sometimes used for these conditions.

Beta-blockers

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

[28], [29], [30], [31], [32], [33], [34], [35]

Alpha-allergic receptor agonists

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

[36], [37], [38], [39], [40], [41], [42], [43]

Anticonvulsants

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

Other antidepressants that act on serotonergic and noradrenergic transmission. Trazodone is an antidepressant that activates the serotonergic system, possibly via its metabolite, meta-chlorophenylpiperazine. Although trazodone is not a first-line drug for most anxiety disorders, it has been shown to be effective in generalized anxiety disorder in a randomized clinical trial. Trazodone has no significant effect on cardiac conduction but may cause orthostatic hypotension. Priapism is a rare but significant side effect of the drug.

A number of new drugs have emerged that have some of the properties of traditional agents used to treat anxiety disorders. These include venlafaxine, which blocks the reuptake of both serotonin and norepinephrine. It may be effective in panic disorder, but experience with its use is limited. Nefazodone, which is structurally related to trazodone and, like it, is metabolized to chlorophenylpiperazine, may also have beneficial effects in some anxiety disorders. Preliminary data indicate that ritanserin, a 5-HT 2 receptor antagonist, is not effective in anxiety disorders. Other serotonergic drugs that may have beneficial effects in anxiety disorders include odansetron, a 5-HT 3 receptor antagonist. Preliminary data suggest that it is effective in generalized anxiety disorder.

[44], [45], [46], [47]

Experimental treatments

Basic research into panic disorder is providing new treatment options for this condition and other anxiety disorders. Based on the hypothesis of a possible role of calcium-dependent mechanisms in the second messenger system in mental disorders, scientists have investigated the efficacy of inositol in panic disorder, obsessive-compulsive disorder, and major depression. Although one small controlled clinical trial showed positive results in the treatment of panic disorder, this therapy is still considered experimental. Based on the data on the relationship between hyperventilation and cerebral blood flow in panic disorder, a study of calcium antagonists was undertaken, which showed some positive effect. Given that cholecystokinin infusion can provoke panic attacks in individuals predisposed to them, cholecystokinin receptor antagonists are currently being developed as potential antipanic and anxiolytic agents.

[ 48 ], [ 49 ]