Selective serotonin reuptake inhibitors

Currently, for the treatment of depression, especially in outpatient practice, relatively new antidepressants are used - selective serotonin reuptake inhibitors (SSRIs), which have significantly fewer side effects than tricyclic antidepressants due to a selective effect on serotonin metabolism (selective inhibition of 5- NT).

SSRIs are represented by drugs such as: fluoxetine (Prozac), fluvoxamine (Fevarin), sertraline (Zoloft, Stimuloton, Asentra), paroxetine (Paxil, Rexetine), cipramil (Citalopram, Cipralex).

Unlike TCAs, a feature of the action of serotonergic antidepressants is their selective effect on the serotonergic system, initially identified in laboratory studies (Wong D., et al., 1974; Fuller R., et al., 1977). The effectiveness of SSRI therapy for depression is at least 65% (Mulrow D., et al., 2000)

Due to the affinity of these drugs and their active metabolites for serotonin receptors, serotonin reuptake is blocked at the level of presynaptic terminals, thereby increasing the concentration of the transmitter in the synaptic cleft, which in turn leads to a decrease in the synthesis and turnover of serotonin (Stark R., et al., 1985).

The selective, but nonspecific for a certain receptor subtype (Stahl S., 1993) action of SSRIs does not always increase the effectiveness of treatment, especially when it comes to the treatment of patients suffering from severe depression (Anderson I., Tomenson B., 1994; Burce M., Prescorn S., 1995).

SSRI drugs have completely different chemical structures and differ from each other in pharmacokinetic parameters, dosages and side effect profiles. The selectivity of 5-HT reuptake inhibition reduces side effects, improves tolerability and reduces drug discontinuation compared with TCAs (Anderson I., Tomenson T., 1994).

Table Comparative characteristics of SSRIs according to the intensity of the antidepressant effect

Note: +++—significant intensity, ++—moderate intensity, +—weak intensity of the effect.

It is necessary to emphasize the relative safety of SSRIs (fewer number and severity of side effects) and greater comfort of treatment (the possibility of carrying out therapy on an outpatient basis).

SSRIs are also characterized by low toxicity (the risk of death in case of poisoning or overdose is almost zero), as well as the possibility of using drugs in this group in patients with contraindications to the use of TCAs (heart rhythm disturbances, difficulty urinating due to prostatic hypertrophy, closed-angle glaucoma) ( Mashkovsky M.D., 1997).

It should be noted that the literature has reported cases of central and peripheral side effects during treatment with SSRIs (Baldessarini R., 1989).

These drugs are more expensive antidepressants than other drugs used to treat depression.

Most selective serotonin reuptake inhibitors (SSRIs) are long-acting and are used in fixed doses. The pharmacokinetics of various representatives of the SSRI group has its own characteristics depending on the age of the patients and somatic burden. Thus, the half-life of fluvoxamine increases slightly in elderly patients and patients with liver pathology (Raghoebar M., Roseboom H., 1988). The half-life of sertraline is also influenced by age (Warrington S.1988), and the effect of fluoxetine is quite significantly affected by the functional capabilities of the liver (Bergstrom M., Lemberg L, et al., 1988).

Clinical trials of SSRIs have demonstrated that they, like TCAs, are an effective treatment for most depressive conditions, including anxiety, sleep disturbances, psychomotor agitation and retardation. (Levine S. et al., 1987, Dunlop S. et al., 1990, Claghorn J., 1992, Kiev A., 1992).

Table Comparative assessment of the additional therapeutic effect of SSRIs

Indications for the use of SSRIs are severe and moderately severe depression (such as simple) with mild anxiety and restlessness (Pujynski S., et al., 1994; Pujynski S., 1996). In addition, SSRIs can be used to treat personality disorders, including anger reactions and impulsivity.

The medical literature emphasizes the sensitivity of vital disturbances to the action of these antidepressants (Laakmann G. et al. 1988).

A number of studies have described that patients in whom melancholy predominated in the structure of the syndrome demonstrated a good therapeutic response when using SSRIs (Reimherr F. et al., 1990, Tignol G. et al., 1992; Mosolov S.N., Kalinin V. .V., 1994).

Considering the good tolerability of these drugs, they are recommended for use in old age.

At the same time, most researchers note a fairly high anxiolytic activity of SSRIs (Amin M. et al., 1989; Kiev A., 1992, Bovin R.Ya., et al. 1995, Ivanov M.V. et al. 1995). At the initial stages of the emergence of SSRIs in the domestic literature, there were indications of low effectiveness, and sometimes even increased anxiety when using SSRIs in patients with anxious depression (Kalinin V.V., Kostyukova E.G., 1994, Lopukhov I.G. et al. , 1994, Mosolov S.N., et al., 1994).

In recent years, studies have been conducted comparing SSRIs with TCAs. Most authors note that the activity of new compounds is comparable to traditional drugs (Guelri J. et al., 1983; Shaw D. et al., 1986; Hale A. et al., 1991, Fontaine R. et al., 1991 ). When comparing SSRIs with TCAs, traditionally used in the treatment of anxiety and depressive conditions, it is usually indicated that the differences in the effectiveness of the studied drugs in their ability to relieve anxiety are not statistically significant (Feighner J., 1985, Laws D. et al., 1990 , Avrutsky G.Ya., Mosolov S.N., 1991, Doogan D., Gailard V., 1992).

According to many authors, SSRIs are effective in some cases when the use of TCAs turned out to be ineffective (Weilburg JB et al., 1989, Beasley CM et al. 1990; Ivanov M.V. et al., 1991; Bovin R.Ya. et al. al., 1992; Serebryakova T.V., 1994; Bovin R.Ya., et al. 1995). According to Beasley C., Sayler M. (1990), patients resistant to TCAs are sensitive to new drugs in 50-60% of cases.

It is necessary to emphasize the greater safety of SSRIs compared to TCAs (fewer number and severity of side effects), greater comfort of treatment (the possibility of carrying out therapy on an outpatient basis) (Boyer W. Feighner J., 1996).

When taking TCAs, 30% of patients are forced to abandon treatment due to the severity of side effects, while when new drugs are prescribed, only 15% of patients have to interrupt their medication (Cooper G., 1988).

S. Montgomery, S. Kasper (1995) showed that the frequency of drug discontinuation due to side effects was 14% of patients treated with SSRIs and 19% with TCAs. The advantage of second-generation antidepressants is especially important during long-term therapy (Medavar T. et al., 1987).

R.Ya. Bovin (1989) points to an increased risk of suicide in the early stages of TCA therapy. While in most studies on SSRIs, the authors pay attention to the high anti-suicide nature of these drugs (Fava M. et al., 1991; Cohn D. et al., 1990; Sacchetti E. et al., 1991) .

In addition to the treatment of depression, attempts are increasingly being made to long-term use of antidepressants (fluoxetine, sertraline) to prevent its relapse.

Cohn GN et al., (1990), given the good tolerability of SA, recommend their use in gerontopsychiatry.

There is no consensus regarding the speed of onset of effect when using SSRIs. According to foreign authors, the clinical effect of SSRIs is detected later than TCAs (Roose S, et al. 1994). At the same time, domestic scientists indicate that SSRIs tend to have a faster onset of therapeutic effect compared to other antidepressants (Avrutsky G.Ya., Mosolov S.N., 1991).

In the SSRI group, various drugs differ in the strength of their action on receptors and the level of selectivity. Moreover, selectivity and potency do not coincide. Paroxetine was found to be a more potent inhibitor of serotonin relapse, while citalopram was more selective. Differences in the selectivity and power of action on receptors determine not only the characteristics of the therapeutic effect of a particular drug, but also the presence of side effects (Thopas D., et al., 1987; Hyttel G., 1993).

Other things being equal, relapses of depression are more likely to occur after treatment with fluoxetine than with paroxetine and after treatment with citalopram than with sertraline; with an almost equal number of relapses during treatment with sertraline and paroxetine.

Since fluvoxamine and paroxetine have a pronounced sedative and anti-anxiety effect, their spectrum of activity is similar to drugs such as amitriptyline or doxepin. Most other drugs, especially fluoxetine, more closely resemble the profile of imipramine, as they have a disinhibitory effect and can increase symptoms of anxiety and restlessness (Caley Ch., 1993; Pujynski S., et al., 1994; Montgomery S., Johnson F., 1995 ). In the domestic literature there are also indications of low effectiveness, and sometimes even increased anxiety when using SSRIs in patients with anxious depression (Kalinin V.V., Kostyukova E.G., 1994, Lopukhov I.G. et al., 1994, Mosolov S.N. et al., 1994).

Due to the disinhibiting effect, such drugs should not be used for anxiety, restlessness, motor disinhibition, insomnia, suicidal thoughts and tendencies. According to S. Pujynski (1996), psychotic forms of depression are a relative contraindication to the use of SSRIs. However, Feighner J., Bouer W (1988), on the contrary, note the positive effect of these drugs even in the psychotic version of depression.

The most common side effects when taking serotonin inhibitors are gastrointestinal disorders: nausea and vomiting, constipation and loose stools. A number of patients experience weight loss.

Table Comparative characteristics of SSRIs by severity of side effects

Note: +++ - significant severity of side effects, ++ - moderate severity of side effects, + - mild severity of side effects

The next most common side effects are: restlessness, anxiety, insomnia, and less commonly, increased drowsiness.

Patients are especially concerned about sexual disorders that may occur when using these drugs. The most common of them: decreased libido, weak erection and difficulty achieving orgasm. In case of severe sexual disorders that have developed during SSRI therapy, the dosage of drugs is usually reduced or discontinued for several days. In some cases, drugs that are serotonin antagonists (cyproheptadine) or drugs that enhance sexual function (yohimbine) are prescribed.

The most frequently mentioned contraindications to taking SSRIs include: hypersensitivity to the drug, pregnancy (cases of treatment of depression during this period with fluoxetine are known) and breastfeeding (the effect of SSRIs on the fetus and child development has been poorly studied), epilepsy, impaired renal and liver function. Drugs in this group cannot be used for poisoning with alcohol and psychotropic drugs. SSRIs should not be used earlier than 2 weeks after the end of therapy with non-selective MAO inhibitors, as well as together with other drugs with serotonergic action (Feihner J., Boyer W., 1996).

All registered SSRIs can provoke a phase change from depressive to manic in individuals with bipolar disease, but such a phase change occurs less frequently than with the use of TCAs (Kharkevich M.Yu., 1996). In addition, when treated with antidepressants for dysthymia, 10% of patients experience mild mania.

Due to the trend towards wider use of serotonin reuptake inhibitors in the treatment of depression, it makes sense to dwell on the characteristics of individual representatives of this group of drugs.

In his practical work, a psychiatrist in a number of cases encounters difficulties in distinguishing the clinical manifestations of depression from the side effects of SSRIs, SSRI withdrawal syndrome, as well as potentially life-threatening serotonin syndrome.

In the practice of a psychiatrist, differential diagnosis of the withdrawal syndrome of these drugs, their side effects and serotonin syndrome with clinical symptoms of depression is of particular importance in the process of SSRI therapy. SSRI withdrawal syndrome, which occurs in the event of a rapid reduction in the dose of the drug or its abrupt withdrawal, is characterized by symptoms such as dizziness, nausea, anxiety and headache. As noted above, side effects of SSRIs usually appear in the first two weeks of therapy and include asthenia, diarrhea, nausea, anxiety, dizziness, sleep disturbance, nervousness and tremor. For serotonin syndrome, which occurs with an overdose of an SSRI or its combination with a TCA, abdominal cramps, psychomotor agitation, diarrhea, convulsions, tachycardia, hypo or hypertension, sweating, and hyperthermia are typical. In depression, the core of the depressive state is anhedonia.

Fluoxetine

One of the first serotonin reuptake inhibitors was fluoxetine (Prozac), which has been actively used since the early 80s to treat various depressive spectrum disorders. In addition, its positive effect in the treatment of bulimia was noted.

Fluoxetine is prescribed at a dose of 20 mg. once a day in the morning, if necessary, increase the dose to 40-80 mg. (in addition to tablet forms, a special solution of fluosetine 4 mg/ml is used abroad).

The drug is well absorbed when administered orally and is demethylated in the liver to form inactive metabolites and pharmacologically active norfluoxetine. Due to the peculiarities of metabolism, the effect of fluoxetine is quite significantly reflected in the functional capabilities of the liver (Bergstrom M., Lemberg L, et al., 1988). It suppresses the activity of hepatic cytochromes P4502D6, and therefore slows down the metabolism of a number of psychotropic drugs, including TCAs, with an increase in their concentration in plasma, which determines the possibility of toxic effects (Creve N., et.al., 1992).

The maximum concentration in the blood when taking fluoxetine is achieved after 6 hours. It has the longest half-life of all SSRIs, which in this case is two to three days, and the half-life of its active metabolite, norfluoxetine, reaches 7-9 days. This circumstance provides an advantage in the treatment of patients who may occasionally forget to take the next dose, but, on the other hand, it complicates the replacement of the drug with other antidepressants (especially MAOIs). It takes several weeks to achieve a stable concentration of the active substance. It was noted that, despite the anxiolytic effect, fluoxetine can increase the manifestations of anxiety and agitation at the initial stage of therapy.

In terms of its spectrum of action, fluoxetine is more reminiscent of the profile of imipramine, since it has a disinhibitory effect and can, as noted above, increase the manifestations of anxiety and restlessness (Caley Ch., 1993; Pujynski S., et al., 1994; Montgomery S., Johnson F., 1995). There is a point of view according to which, due to the disinhibitory effect, fluoxetine should not be used for anxiety, restlessness, motor disinhibition, insomnia, suicidal thoughts and tendencies, however, recent studies have shown that taking fluoxetine does not increase the risk of suicide (Freemante N., et.al ., 2000).

Fluoxetine (Prozac), compared to other SSRIs, eliminates signs of depression much more slowly (within 2-3 weeks), however, its final effect turned out to be similar to the effect of other drugs of this class (Edwards J., Anderson I., 1999). There are observations that fluoxetine is approximately equal to TCAs in its effectiveness in relieving symptoms of depression (Beasley C., et al., 1991).

At the same time, there is a point of view according to which fluoxetine is inferior to other SSRIs in its ability to relieve general manifestations of depression (Williams J., et al., 2000).

In the first days of using fluoxetine, and possibly also at further stages of treatment, nausea, akathisia, headaches, impaired visual acuity, and allergic skin reactions may be observed. Sexual dysfunctions have been reported when taking fluosetine (Guthrie S., 1991; De Vane C. 1994; Pujynski S., 1996).

Fluvoxamine

Fluvoxamine (fevarin), as a selective serotonin reuptake inhibitor, has a distinctly activating, mood-enhancing effect, it calms, stabilizes the activity of the autonomic system and can be recommended for a combination of depression and anxiety. In addition, the positive aspect of fluvoxamine treatment is its relatively rapid onset and smooth action, which, as a rule, contributes to the establishment of a good relationship between the patient and his attending physician.

Fluvoxamine is prescribed in a dose of 50 mg. per day once in the evening. The dose of the drug can be increased to 100 mg. (average dose of effectiveness) for 5-7 days. If necessary, the dosage of the drug can be further increased at intervals of 2-4 weeks (maximum daily dosage - 500 mg), starting with a dose of 150 mg. the drug is prescribed several times a day.

The active metabolites of fluvoxamine are unknown. The average half-life is 20 hours, plasma concentrations are not proportional to the dose taken

In most cases, symptoms of an anxiety disorder are eliminated earlier than those of a depressive disorder. This was clinically manifested by an improvement in the general condition of the patients, leading them to greater composure, confidence and external calm. The effectiveness of this drug is noted in patients with obsessive disorders and social phobia, in particular in childhood.

Adding fluvoxamine to atypical neuroleptics can reduce the severity of primary negative symptoms in patients with chronic schizophrenia. At the same time, comparative studies have shown that among the group of selective serotonin reuptake inhibitors, it has the greatest number of side effects (Freemante N., et al., 2000), sertraline has the least (Edwards J., Anderson I., 1999 ).

How dangerous is taking antidepressants? What are the side effects?

Antidepressants cause some side effects. In drugs from different groups they are expressed to varying degrees. For example, SSRIs are the safest; most patients who take them do not experience any problems. At the same time, MAOIs can cause life-threatening side effects. They are incompatible with some types of medications and even food.

Unfortunately, the safest drugs are not always effective. In such cases, there is nothing left but to resort to “heavy artillery.” The doctor must carefully assess the patient's condition and prescribe the most appropriate medications in optimal dosages.

Sometimes in patients under 25 years of age, antidepressants increase suicidal tendencies, especially in the first weeks of use and when the dosage is changed. However, in the long term, they tend to improve mood and reduce the likelihood of suicide.

Citalopram

Citalopram has a significantly higher level of selectivity for serotonin transporters compared to norepinephrine and dopamine transporters.

The drug is prescribed in a dose of 20 mg. per day once a day in the morning. For most patients, this dose is the most effective; the maximum daily dose of the drug is 60 mg.

Citalopram practically does not enter into drug interactions, due to the fact that it has little effect on the activity of some liver enzymes (cytochrome P450 enzyme system). Therefore, it is often used in the treatment of depressive conditions that develop as a result of chronic somatic diseases. Interdrug interactions of the drug are minimal. Under the influence of cytochrome P450, citalopram is converted into two main metabolites: demethylcitalopram and didemethylcitalopram. These metabolites have pharmacological activity, but much less than that of citalopram itself. The half-life of citalopram is 30 hours. It is characterized by a linear dependence of plasma concentrations depending on the dose in the therapeutic interval. For the treatment of severe depression, the dose of the drug should be increased.

The use of citalopram is recommended in general medical practice, in elderly patients and persons who have suffered a cerebral stroke.

When prescribing citalopram, the percentage of men with sexual dysfunction, a side effect that is relatively common when prescribing drugs in this group, turned out to be extremely small. Headache and nausea were the most common side effects of citalopram treatment during the first two weeks of treatment.

How do you know which antidepressant is best to start with?

Initially, the doctor prescribes the drug that, in his opinion, is best suited for a particular patient. It is impossible to know for sure what will work more effectively, but there are some factors that you can focus on: the type and symptoms of depression, side effects of medications, the general health of the patient, and concomitant diseases.

If you have family members with depression and certain medications work well for them, chances are the same medications will work for you.

Antidepressants can be prescribed during pregnancy and breastfeeding, but with caution. The doctor must carefully weigh the possible risks.

Sertraline

Sertraline (Zoloft, Stimuloton, Asentra) is characterized by a thymoanaleptic (anxiolytic) effect of moderate severity. There are no vegetative stabilizing, sedative, timerectic, adrenergic and anticholinergic (muscarinic) effects. The drug does not affect psychomotor functions, has a weak antiphobic and very weak hypotensive effect.

Indications for use are mild to moderately severe melancholy depression with secondary anxiety and somatoform disorders. After obtaining a satisfactory effect, continuing treatment with sertraline helps prevent relapse of depression or its subsequent occurrence.

Sertraline is also used to treat obsessive-compulsive disorder (OCD).

As a rule, the antidepressant effect occurs after one week of therapy.

After achieving the initial effect, long-term treatment with sertraline for up to 2 years ensures its sufficient effectiveness and good tolerability. Sertraline is used to treat panic disorders and post-traumatic stress disorder syndrome (PTSD). The initial therapeutic effect in this case may appear within 7 days, but the full effect is usually achieved later - after 2-4 weeks (possibly over a longer period of time, especially with OCD). There is a point of view according to which the drug usually reduces secondary anxiety associated with melancholy depression.

Sertraline (Zoloft, Stimuloton) is a relatively low-toxic antidepressant from the SSRI group; it is used in child psychiatry, as well as in cases of depressive spectrum disorders that develop after an acute episode of schizophrenia.

Sertraline is prescribed in a dose of 50 mg. per day (usually once a day in the morning, regardless of meals). The dose can be increased by 50 mg. in Week. Recommended daily doses: for inpatient treatment of depression - 50-100 mg, for outpatient use - 25-50 mg. If necessary, the dose is increased at intervals of 2-4 weeks (maximum daily dose - 200 mg).

At therapeutic doses, sertraline inhibits the uptake of serotonin by platelets. It is extensively metabolized in the liver, approximately 98% of it is present in the body in protein-bound form, and its main metabolite has weak pharmacological activity. Unlike most antidepressants, it binds preferentially to a1-glycoprotein, whereas other drugs interact primarily with albumin.

The half-life of sertraline is influenced by age. In children, sertraline metabolism is more active (Warrington S.1988). Considering the latter circumstance, it is recommended to use the drug in children in a lower dose to avoid excessive levels of its concentration in plasma. At the same time, according to other authors, the pharmacokinetic profile in adolescents and elderly people does not differ significantly from the profile of patients aged 18 to 65 years.

Sertraline is slowly absorbed over 4-6 hours, eliminated through the gastrointestinal tract and kidneys, the equilibrium concentration of the drug is achieved within one week after the start of treatment.

The average half-life of sertraline is 22-36 hours. Steady-state concentrations of sertraline are established after 1 week of treatment.

Kidney pathology has almost no effect on the clearance of sertraline. At the same time, with liver pathology, the half-life of sertraline in serum, as well as its concentration in plasma, increases by almost 50%.

Side effects: tremor, nausea, dry mouth, diarrhea. Typically, side effects resolve spontaneously by the end of 4 weeks of therapy. Early unwanted side effects are especially common in the treatment of panic disorders.

Contraindications to the use of the drug are liver and kidney diseases with impaired function. After discontinuation of the drug, MAOIs are prescribed no earlier than 5 weeks later.

With chronic use of sertraline, addiction develops to it, since its prolonged use leads to a decrease in the number of its receptors (Anthony P., et al., 2002).

The use of selective serotonin reuptake inhibitors in neurological practice

The development of depression can be situationally determined, but in neurological patients it is usually caused by organic brain damage or an imbalance of neurotransmitter systems. Patients with chronic neurological diseases are more susceptible to depression than patients with somatic pathology [15]. Neurological diseases that can cause depression are numerous. This disorder is one of the common symptoms in Parkinson's disease, parkinsonism syndrome, acute and chronic cerebrovascular diseases, degenerative dementias, pain syndromes, multiple sclerosis, and brain tumors [18,19,21,26]. Encephalopathy, which develops in the late stages of liver and kidney failure, a number of endocrine, hematological and systemic disorders, and alcoholism, is also often accompanied by the development of depression, which is associated with hypoxic, dysmetabolic and toxic damage to the brain. Depressive disorders can be caused by long-term use of medications. The list of these drugs is quite large, and many are widely used. These are b-blockers, calcium channel blockers, corticosteroids, anabolic steroids, oral contraceptives, cardiac glycosides, barbiturates, clonazepam. Neuroleptic depression occurs during long-term use of large doses of antipsychotics (buterophenones, fluphenazine, chlorpromazine, risperidone) and is accompanied by extrapyramidal disorders [2,6,26]. Depressive disorders can occur under the guise of dementia and may accompany its development. At the same time, depression is often observed in vascular dementia and less often in Alzheimer’s disease [4]. The modern pathomorphosis of depression has led to a change in its clinical picture, an increase in the frequency of atypical, hidden, erased forms. Currently, the proportion of typical cases is only 10%, and the bulk of depression occurs atypically. In the practice of a neurologist, depression most often appears under the guise of vegetative dystonia syndrome, chronic pain syndromes, insomnia, and neuroendocrine disorders [15,29,32]. The most striking manifestations of vegetative dystonia syndrome include vegetative crises (panic attacks) [6]. Another very common mask for depression is chronic pain syndromes, including in children. Depression accompanies and can intensify conversion disorders within psychogenic and psychoorganic diseases. The mechanisms underlying depression are currently being actively studied. It has been shown that not only the limbic system, but also cortical structures are involved in emotional reactions. Particular importance is attached to the frontal lobes of the brain [30]. In a number of mental disorders that have traditionally been considered “functional,” morphological changes in the nervous tissue have been identified, not only at the microstructural level (in the form of atrophy of synapses, shortening of dendrites and death of some neurons), but also at the macrostructural level (in the form of a decrease in the volume of the hippocampus and some other parts of the brain). Moreover, in recent years it has been shown that pathological processes in the brain can be partially reversible under the influence of therapy with drugs that have neurotrophic and neuroprotective properties [15,16]. According to some data, with depression, signs of hyperreactivity of the hypothalamic-pituitary-adrenal system are found; there is also information about an increase in the number of neurons secreting corticotropin-releasing factor. 33–66% of patients with depression have adrenal hyperplasia, and cortisol levels are elevated and positively correlate with the severity of the condition. Chronic hypercortisolemia contributes to the formation of insulin resistance, arterial hypertension, overproduction of steroids, hyperglycemia, hypercholesterolemia, which increase the risk of cardiovascular complications [34]. According to experimental data, in situations of chronic pain, emotional or social stress (which are models of depression), the volume of the hippocampus statistically significantly decreases (up to 10%, as in patients with depression), the number of granular cells in the dentate gyrus decreases, and in the CA1 and CA3 fields of the hippocampus the size of pyramidal cell bodies decreases and atrophy of their dendrites develops (up to 50% of the length), which leads to disruption of the normal functioning of the limbic system and its connections with other parts of the brain [11]. Thus, the effects of chronic stress and affective disorders in humans, as well as behavior disorders similar to depression in animals, are associated with damage and death of brain cells. These findings are consistent with the idea that anxiety disorders caused by stressors may not only precede, but also cause, at least some forms of depressive disorders. The predominant localization of morphological changes primarily in the limbic system, basal ganglia and rostral cortex may explain the disorders of both emotional, motor and cognitive functions that develop with depression. It is assumed that these morphological changes are a consequence of the cytotoxic action of a number of agents, primarily excitatory amino acids and, possibly, calcium [11]. The development of excitotoxicity is greatly facilitated by the increased content of corticosteroids (mainly cortisol) and deficiency of g-aminobutyric acid noted in depression [2]. It is possible that a number of disorders are based on neurotransmitter dysfunctions, most likely associated with a deficiency of central serotonergic and noradrenergic structures. Some authors also mention the role of hypoglycemia and a possible decrease in cerebral blood flow in the pathogenesis of depression. Of particular importance in the pathogenesis of depression in the elderly is given to vascular damage to the subcortical-frontal connections with the occurrence, in addition to depression, of impaired executive functions, psychomotor retardation, and apathy. Currently, several pathophysiological mechanisms of the influence of depression on the state of the cardiovascular system in the elderly are being considered. One of the main pathological processes in depressive disorders is an imbalance of the autonomic nervous system with activation of the sympathetic department. Increased release of catecholamines leads to an increase in myocardial oxygen demand due to an increase in heart rate, blood pressure and the force of myocardial contraction. It has been established that the appearance of depression in patients with diseases of the cardiovascular system is accompanied by a significant decrease in heart rate variability, reflecting the deterioration of regulatory mechanisms and a decrease in the body’s adaptive capabilities in response to stress [13,22]. An achievement of neuroscience in recent years has been evidence that the destructive processes occurring in affective disorders are partially reversible under the influence of successful therapy with drugs that exhibit neurotrophic and neuroprotective properties [17]. The restoration of brain tissue and its functions is associated with the reorganization and formation of new synapses, lengthening and sprouting of dendrites and axons with neurogenesis. The effect of antidepressants is not limited to their regulatory influence on the content of monoaminergic neurotransmitters in the synaptic cleft and in presynaptic structures, as well as on the number and sensitivity of postsynaptic receptors, but also extends to intracellular cascades of neurochemical processes. One of the compounds formed in this case is cAMP element-binding protein (CREB), which activates the “late” gene of the brain derived neurotrophic factor (BDNF), which, in turn, enhances the expression of the gene for the main cytoprotective protein bcl-2, suppresses apoptosis, which promotes the restoration and survival of neurons [15]. Symptoms of depression may be obvious. Along with depression (in typical cases in the form of vital melancholy), depression includes ideational and motor inhibition with a decrease in motivation for action or anxious arousal (up to agitation). The mental hyperalgesia (mental pain) characteristic of depressed patients is associated with feelings of guilt, decreased self-esteem, suicidal thoughts, and a painful physical feeling is associated with “somatic” symptoms, such as sleep disorders with difficulty falling asleep and early awakenings; a sharp decrease in appetite and body weight; decreased libido and menstrual irregularities, including amenorrhea, etc. Low mood usually persists throughout the entire depressive attack. A typical sign of depression is also a circadian rhythm with improvement or (less often) worsening of well-being in the evening. Atypical manifestations of depression are the absence in some cases of complaints of low mood or the patient’s fixation on excitability or anxiety rather than low mood. Pain and psychosomatic disturbances may also be atypical manifestations of depression. The diagnostic criteria for masked depression are: frequent discrepancy between the patient’s complaints and the nature of the morphological changes; the possibility of the absence of objective signs of somatic disease; frequency (seasonality) of manifestation of disease symptoms; remitting course with a possible change in phases of exacerbations and relapses; connection between well-being and the biological rhythm of physiological functions (patients feel better in the evening); frequent repeated requests for medical care; insufficient effectiveness of symptomatic therapy or lack thereof; improvement of well-being while taking antidepressants. The identification of depressive disorders is greatly facilitated by the use of psychometric scales and tests, the use of which can reduce the doctor’s time spent on examination. The most well-known among the subjective psychometric scales for screening depression are the Hospital Anxiety and Depression Scale [A. Zigmond, 1983] Zung scale [WW Zung, 1965], Beck Depression Inventory [A. Beck, 1961] [2,3,17,20,28,34,35]. The basis for diagnosing depression is the assessment of medical history and clinical data. The results of paraclinical examination methods (including neuroimaging) are not of great importance; they only help to exclude neurological or somatic causes of the disease. The detection rate of depression by general practitioners does not exceed 50% [16,35]. To a certain extent, this is due to the low specificity of the clinical manifestations of this disease. For example, weight loss and increased fatigue can occur not only with depression, but also with cancer, diabetes and thyroid diseases. In neurological practice, diagnosing depression is difficult not only because of the frequent combination of neurological symptoms and depression when the central nervous system is damaged, but also because of the influence of neurological disease on the emotional behavior of the patient. Thus, the slowness and paucity of movements characteristic of parkinsonism, combined with a violation of the rhythm and intonation of speech, makes it difficult to correctly assess the emotional status. This task becomes even more complicated in patients with severe cognitive or speech disorders of various origins [4,7]. Complaints of chronic pain, one of the most common “masks” of depression, deserve close attention. A combination of depression and chronic pain syndromes is observed in 50–60% of patients. Antidepressant therapy is the mainstay of treatment for depressive conditions. The question of starting drug therapy becomes relevant if symptoms persist for 2–4 weeks or more. It should be noted that about 50% of cases of treatment failure are associated with its inadequate use [5,6]. The most common mistakes, in addition to untimely initiation of treatment, as well as insufficient consideration of clinical indications and contraindications for the drug, are the implementation of routine (without taking into account individual characteristics) low-dose therapy or, conversely, frequent changes, “juggling” drugs without observing the required exposure duration, or premature discontinuation of therapy, or patient ignoring medical prescriptions [12]. As is known, in many cases the clinical effect develops gradually, and suppression of current psychopathological symptoms does not yet mean achieving stable remission and the end of treatment. The effect of antidepressants usually does not appear immediately, but several weeks (usually from 3 to 6) after the start of treatment, about which the patient must be informed in a timely manner. After regression of depression symptoms, therapy is continued for 4–5 months. Treatment failure associated with true drug resistance is very rare, therefore, only if the effect of the selected drug in an adequate dose does not appear after 6–8 weeks, switch to an antidepressant of another group. It is important to emphasize that in most cases, the lack of effect of treatment is not due to true drug resistance, but to an insufficient dose or short duration of therapy, as well as non-compliance with medical prescriptions. The possibility of psychotherapy, which, if necessary, can be supplemented with antidepressants, is currently being discussed, but the effectiveness of such a therapeutic approach requires further study. In neurological practice, one often has to deal with restrictive tactics of using antidepressants [6]. Of those with an epidemiological diagnosis of depression in outpatient practice (scoring more than 18 points on the depression scale of the Center for Epidemiological Studies), 72.2% of patients received treatment. However, as a rule, herbal medicines and tranquilizers were used. Only 8.7% of patients with depression took antidepressants. If drugs of this group were nevertheless prescribed, then, as a rule, in fairly low daily doses [6]. The Russian multicenter study Compass found that neurologists are only slightly more likely than other specialists (generalists, cardiologists) to prescribe any therapy for depressive conditions in general (74% versus 67.2 and 67.8%, respectively) and thymoleptics, in in particular (14.1% versus 7.2 and 6.5%, respectively) [5]. Thus, the role of drug treatment for depression requires additional discussion. Antidepressants are medications that help reduce ideational, motor and somato-vegetative disorders caused by depression. The clinical effect of modern antidepressants is based on the correction of the functions of the serotonergic and noradrenergic systems of the brain. The classification of antidepressants according to the mechanism of neurochemical action is very convenient (Table 1). Among the clinical classifications of antidepressants, the most widespread is the convenient and simple classification of P. Kielholtz, distinguishing drugs with predominantly sedative, stimulating or balanced effects (Table 2). The scientific development of modern antidepressants, on the one hand, is moving towards increasing the specificity of their biochemical action. In particular, selective agonists and antagonists of monoamine neuroreceptors are synthesized and tested. Substances have been found that selectively act on certain types of receptors (5HT1, 5HT2, and 5HT3 serotonin receptors). Examples include direct agonists of 5HT1a serotonin receptors (flesinoxan, ipsapirone, etc.). At the same time, there remains a tendency to develop agents with a broad effect on various monoamine systems with minimal effect on receptors, which are associated with the development of side effects (milnacipran, venlafaxine, nefazodone, mirtazapine, duloxetine, etc.). And finally, the mechanism of action of some drugs with thymoanaleptic activity is not directly related to the monoamine system or is not clear enough (for example, tianeptine, alprazolam, S-adenosylmethionine, neuropeptides, etc.) [12,17,27,33]. Among the most studied on the pharmaceutical market over the past two decades, the so-called third-generation antidepressants, which are representatives of a new class of pharmacological agents, selective serotonin reuptake inhibitors, have become widespread. These include, in particular, fluvoxamine [3,12,14]. Unlike tricyclic antidepressants, selective serotonin reuptake inhibitors are more targeted to a wide range of neurotic-level depressive conditions. They have a greater spectrum of psychotropic effects with fewer side effects. Nuclear variants of melancholic endogenous depression syndrome with typically circus symptoms, severe (psychotic) depression and depressive -delusional conditions react worse to therapy for the inhibitors of the reverse capture of serotonin. On the contrary, depressive conditions with exhausive -phobic, hypochondriacal and alarming symptoms of a neurotic level are treated quite successfully. In addition to depressions with atypical symptoms, the high efficiency of serotonergic antidepressants was shown with anxious and exhaustively and compulsive disorders in pure form or coomorbitis with depression, as well as with panic disorder, stupid stressful disorders, social phobias, somatoform disorders and other alarming disorders [1.10 [1.110 [1.110 , 12,14,27]. Analysis of a number of randomized tests of comparing the clinical effect of the group of selective neuronal capture inhibitors with tricyclic antidepressants, such as Imipramin, discovered the similar positive effects of non -elective and selective drugs. When summing up the results of all clinical trials, it became clear that selective drugs have no clear advantages over reference tricyclic antidepressants. The negative effects of the drugs of these groups differ significantly. For example, the likelihood of a sedative effect, anticholinergic effect and heart rhythm disorders when using selective inhibitors of the reverse neuronal capture of serotonin is less than when using conventional antidepressants. On the other hand, the negative effects of selective inhibitors of the reverse neuronal capture affect the gastrointestinal tract, causing nausea and diarrhea, and can also lead to insomnia, excitement, extrapyramidal disorders (drug parkinsonism) and cancellation syndrome. When comparing the negative effects of selective inhibitors of the reverse neuronal capture and ordinary antidepressants, one cannot but come to the conclusion that one group of negative effects changes to another and there is no difference in the number of people who can take these two groups of antidepressants. In the course of 58 clinical trials, patients who stopped taking antidepressants were studied, and there was no significant difference between selective inhibitors of the reverse neuronal capture and ordinary antidepressants. Thus, the numerous scientific studies of this group of drugs, including those conducted in comparison with the reference tricyclic antidepressants traditionally used in psychiatry and neurology in the treatment of depression (amitripplin, Imipramine, clomipramine, etc.), showed their high therapeutic efficiency, comparable with tricyclicclical compounds with smaller side phenomena [2,6,8,9,12,14,31,33]. However, despite the belonging to one group of chemical compounds, the spectrum of antidepressant activity of various selective inhibitors of reverse neuronal capture has its own characteristics, which determine the pre -emptive indications for their individual purpose and deserve discussions. Fluvkamin is the ancestor of the antidepressants of the selective inhibitors of the reverse capture of serotonin, the first and most widely studied drug of this group. Fluvkamin is registered in more than 80 countries, has the largest (among antidepressants) database of clinical studies, including a description of the treatment results of 38 thousand patients. To date, more than 5,000 scientific works on the study of the drug have been published. The drug has been successfully used since 1983 in the treatment of depressive disorders of varying severity, as well as the so -called border mental disorders (anxious, panic, obsessive -compulsive, behavioral, etc., including children from 8 years old) [10]. The mechanism of action of fluvkasamin is associated with the electoral inhibiting of the reverse capture of serotonin neurons of the brain and is characterized by minimal effects on the norepinephrine transmission. Fluvkamin has an unexpressed ability to contact a - enerers, b - adrenergic, histaminergic, muscarinal cholinergic, dopaminergic or serotonergic receptors. Fluvovkamin has pronounced anxiolytic and sedative properties and serves as a drug of choice for the treatment of depression in combination with anxiety, panic and psychomotor agitation. The drug is also distinguished by moderate psychostimulating activity, which is the result of the lack of suicidogenicity, hypermostation, increased irritability, sleep disturbances. A powerful vegetostabilizing effect of fluvcamine is especially important in the treatment of neurotic, somatized depression and distility. The lack of behavioral toxicity does not violate attention, memory and cognitive functions. Fluvkamin is an effective antidepressant in the treatment of depression of various types and varying degrees of severity. This is confirmed, in particular, by the data of meta -analysis, according to which Fluvovkamin is the drug of choice in the treatment of patients with severe depression in a hospital. In addition, the effectiveness of flovksamin in the prevention of relapses of depression has been proved. After the course of treatment with the drug, relapses developed three times less, and the period of remission before the first relapse was twice as long as when using a placebo. A pronounced anti -ranging effect of fluvcamamine eliminates or reduces pathological attraction to alcohol. In psychiatric practice, the drug demonstrated good effectiveness in the correction of negative (deficiency) symptoms in patients with schizophrenia. In the clinical department of endogenous mental disorders and the affective states of the Scientific Center for the Mental Health of the RAMS, clinical study of fluoxetine, fluvkamin, cerrodin and paroxetine took place in different periods. In total, these drugs underwent course treatment of 129 patients with endogenous depression. Fluvovsamin made it possible to reduce the severity of depression in this group to an easy degree by the 5th day of treatment, but as a “significant” therapeutic effect was recorded after 14 days (the second week) of treatment, and by the end of the course treatment the total point of the symptoms of depression on the Hamilton scale decreased by 64.6%. Fluvkamin showed a good therapeutic effect equally with depressive conditions of mild and moderate severity, which, subject to its good knowledge, makes it the drug of choice in this group of conditions. The thymoleptic effect of fluvcasmine manifested itself at the level of 76.1%, while the sedative -quiniolytic and stimulating components of the fluvsksamin action were almost the same and less deep, they were manifested at 67.8 and 64.5%, respectively [14]. Izmailova I.G. et al. Assessed the effect of fluvkasamin in a group of children with a headache of tension. The initial dose of fluvkasamin was 12.5 mg at night, with a further gradual increase in the dose of 12.5 mg every two days before the optimal daily dose - 50–75 mg. The course of treatment was 1.5–2 months. The specified pharmacotherapy was combined with massage, psychotherapy, physiotherapy. The clinical effect in the form of a decrease in headache and improvement of moods began to be noted by the end of the first week of treatment, no side effects were observed. After 1.5 months of therapy in 25 children, the existing violations were completely stopped; 5 children had a decrease in the intensity and frequency of Tsephalgia attacks. The dynamic study of psycho -vegetative status has shown a reliable decrease in astheno -vegetative and anxious -depressive disorders to close to normal indicators, which confirms the anxiolytic, antidepressant, vegetative and mild anti -aastenic effect of the drug in a children's population. Katamnez (6 months) confirmed the preservation of the achieved results in 20 children. Antidepressants of various structures have been traditionally used for chronic alcohol disease. A number of domestic and European researchers are convincingly expressed in favor of central serotonin insufficiency as the main neurochemical mechanism for the development of depression in alcoholism. Using antidepressants, you can not only affect depressive disorders, but also stop pathological attraction to alcohol. And in this regard, selective inhibitors of the reverse capture of serotonin, which reduce the pathological attraction to alcohol, are most preferable. According to numerous domestic data, it is Fluvkamin - an antidepressant of “predominantly sedative effects with expressed not only thymoanaleptic, but also vegetostabilizing and anxiolytic effects” - the most preferable for chronic alcoholism and drug addiction due to high comorbitsias of alcohol depresses of anxious, phobic, somnological, and somnological, co -somnological dishes , a Also aggressive and suicidal behavior [10]. The good tolerance of fluvcamamine, in particular, the lack of a sedative side effect, allows it to be used in outpatient practice, without reducing the quality of life of the patient. It is important to emphasize that Fluvovsamin is not only the most studied, but also economically most affordable drug from the group of selective serotonin capture inhibitors. The most important condition for the success of treatment is a rational combination of pharmacotherapy with socio -rehabilitation and psychotherapeutic measures, including psycho -educational work with the active involvement of the patient and his relatives in the medical process.

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