Valdoxan tablets: instructions for use, price, reviews. Indications for use

Pharmacodynamics and pharmacokinetics

Agomelatine is a substance with an antidepressant effect aimed at validated models of depression and some other abnormalities in the activity of the nervous system. At the same time, drugs created on its basis do not have a strong negative effect on the activity of other body systems.

Taking agomelatine helps normalize sleep structure, lower body temperature and improve the release of melatonin . The drug can be used to treat nervous system disorders of varying degrees of complexity, therefore both short-term and long-term therapy is allowed.

As a result of internal administration, absorption occurs quite quickly and almost completely. The maximum concentration in plasma is achieved 1-2 hours after administration of the drug. When distributed within the body, the substance is almost completely bound to plasma proteins, regardless of the concentration of the drug, the age of the patient, or the presence of renal impairment. A fairly rapid elimination of the drug from the body was noted, mainly in the form of metabolites through the kidneys. A small part of the unchanged substance is also excreted in the urine.

Valdoxan 25 mg 28 pcs. film-coated tablets

Composition and release form Valdoxan 25 mg 28 pcs. film-coated tablets

Tablets - 1 tablet:

active substance: agomelatine 25 mg;
Excipients: lactose monohydrate 61.84 mg, magnesium stearate 1.3 mg, corn starch 26.0 mg, Povidone-K30 9.1 mg, colloidal silicon dioxide 0.26 mg, sodium carboxymethyl starch 3.9 mg, stearic acid 2 .6 mg;
Film coating: glycerol 0.19665 mg, hypromellose 3.26871 mg, iron dye yellow oxide 0.19509 mg, macrogol 6000 0.20872 mg, magnesium stearate 0.19665 mg, titanium dioxide 0.43418 mg.

The design of the company logo on the tablet is applied with blue paint, which contains shellac, propylene glycol, and indigo carmine aluminum varnish.

14 tablets per blister (PVC/Al), 1, 2, 7 blisters with instructions for medical use per cardboard pack.

Packaging for hospitals:

10 tablets per blister (PVC/Al). 10 blisters with instructions for medical use per cardboard pack.

When packaging (packing) at the Russian enterprise Serdix LLC:

14 tablets per blister (PVC/Al). 1.2 blisters with instructions for medical use per cardboard pack.

10 tablets per blister (PVC/Al). 10 blisters with instructions for medical use per cardboard pack.

Packaging for hospitals:

14 tablets per blister (PVC/Al). 7 blisters with instructions for medical use per cardboard pack.

Description of the dosage form

Oblong film-coated tablets, orange-yellow in color with a blue company logo on one side.

Directions for use and doses

Valdoxan is prescribed at a dose of 25 mg per day (1 tablet), taken in the evening. The attending physician can individually prescribe a dose of 50 mg for daily use.

Pharmacodynamics

Antidepressant, melatonin agonist (MT1 and MT2 receptors) and serotonin antagonist (5-HT2c receptors). Agomelatine is active in validated models of depression (learned helplessness test, despair test, moderate chronic stress), in models with heart rate desynchronization, as well as in experimental situations of anxiety and stress. It has been shown that agomelatine does not affect the uptake of monamines and has no affinity for alpha, beta adrenergic receptors, histamine receptors, cholinergic receptors, dopamine and benzodiazepine receptors; This explains the absence of agomelatine’s side effects on the gastrointestinal tract, sexual functions and cardiovascular system, which are characteristic of other antidepressants. Agomelatine, due to its antagonistic effect on serotonin 5-HT2c receptors, enhances the release of dopamine and norepinephrine, especially in the prefrontal cortex.

In experimental animal studies with simulated Delayed Sleep Phase Syndrome in blind and aged animals, agomelatine was shown to restore synchronization of circadian rhythms through stimulation of melatonin receptors. In case of chronic stress, agomelatine prevents the occurrence of “broken” (fragmented) sleep. In experiments on healthy volunteers, agomelatine did not disrupt the normal structure of sleep and had a beneficial effect on sleep in patients with depression. In therapeutic doses, agomelatine prevented the development of insomnia and memory impairment from the moment of taking the drug until the morning. Agomelatine is not addictive, as demonstrated in a study of healthy volunteers using a visual analogue scale or the Addiction Research Center Inventory (ARCI 49 check-list). Agomelatine has also been assessed for withdrawal symptoms in depressed patients using the Discontinuation Emergent Signs and Symptoms (DESS) Questionnaire. It has been established that withdrawal syndrome does not develop even with abrupt cessation of treatment. Agomelatine does not affect body weight.

Agomelatine's clinical development program examined its efficacy and safety in major depressive disorder. In a placebo comparative controlled study, 4500 patients were examined, of whom 2500 received the drug for 6 weeks to a year. Agomelatine was statistically significantly more effective compared to placebo, with the antidepressant effect occurring within 2 weeks (efficacy range: from 49.1 to 61% versus 34.3 to 46.3% in the placebo group). Reliable data were also obtained on the effectiveness of agomelatine in patients with more severe forms of depressive disorder (Hamilton scale scores >=25), constituting more than 2/3 of the population. Active control studies confirmed the results. Agomelatine was also effective for initially high levels of anxiety, as well as for combined anxiety and depressive disorders. The effect of agomelatine on the sexual function of patients with depression with a relapsing course of the disease was studied. The Sex Effects Scale (SEXFX) was used. Agomelatine has not been shown to cause sexual dysfunction and does not affect arousal or orgasm. In patients with depression, starting from the second week of treatment, agomelatine statistically significantly improved the process of falling asleep, without causing subsequent daytime lethargy (the Leeds Questionnaire was used).

Pharmacokinetics

Suction

After oral administration, agomelatine is quickly and well (>80%) absorbed from the gastrointestinal tract. Cmax in plasma is achieved 1-2 hours after administration. Bioavailability at a therapeutic dose taken orally is approximately 3% and varies depending on the first pass effect through the liver and individual differences in CYP1A2 activity parameters. When prescribed in therapeutic doses, the therapeutic concentration of the drug increased in proportion to the dose. Meal intake (both regular and high-fat) did not affect either bioavailability or rate of absorption.

Distribution

The volume of distribution at equilibrium was about 35 liters. Plasma protein binding is 95%, regardless of drug concentration, age or the presence of renal failure.

Metabolism

After oral administration, agomelatine undergoes rapid oxidation, mainly due to CYP1A2 (90%) and CYP2C9 (10%). The main metabolites in the form of hydroxylated and demethylated agomelatine are inactive, quickly bind and are excreted in the urine. Removal of T1/2 from plasma is from 1 to 2 hours. Removal occurs quickly. High and mostly metabolic Cl is about 1100 ml/min. Excretion occurs mainly in urine (80%) and in the form of metabolites. The amount of unchanged drug in the urine is insignificant. With repeated administration of the drug, the kinetics do not change.

Pharmacokinetics in special clinical situations

The dependence of the pharmacokinetics of the drug on age has not been identified. Since no significant changes in pharmacokinetics are observed in patients with renal failure, special selection of drug doses for this category of patients is not required. When comparing the effect of the drug in healthy volunteers (matched for age, body weight and number of cigarettes smoked) with patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) degrees of liver failure, in the latter an increase in the duration of action of the drug was observed when prescribed at a dose of 25 mg/day. No unusual adverse reactions were observed.

Indications for use Valdoxan 25 mg 28 pcs. film-coated tablets

"Valdoxan" is a drug with an antidepressant effect, used in the complex treatment of severe depressive disorder.

Contraindications

You should not take Valdoxan if you have an individual sensitivity to the components of the dietary supplement. A contraindication is considered to be severe renal failure.

Application Valdoxan 25 mg 28 pcs. film-coated tablets during pregnancy and breastfeeding

During pregnancy, Valdoxan is prescribed with caution; lactation should be stopped during the course of therapy. Persons under 18 years of age are not recommended to take the drug due to the lack of sufficient clinical studies in this group of patients.

special instructions

Liver function monitoring:

Cases of liver damage have been reported, including liver failure (leading in exceptional cases to death or requiring liver transplantation in patients with pre-existing risk factors for liver damage), elevation of liver enzymes more than 10 times the upper limit of normal, hepatitis and jaundice in patients taking Valdoxan® during the post-registration period. Most of these disorders occurred in the first months of treatment. The nature of liver damage appears to be primarily hepatocellular. As a rule, after cessation of therapy, transaminase levels returned to normal values. Caution should be exercised before starting treatment and close monitoring during treatment in all patients, especially those with risk factors for liver disease or those receiving concomitant therapy with drugs that can cause liver damage.

Before starting therapy

Treatment with Valdoxan® should be prescribed only after a careful assessment of the expected benefit to possible risk in patients with risk factors for developing liver dysfunction, such as obesity/overweight/non-alcoholic fatty liver disease, diabetes, alcohol abuse and taking drugs that can cause liver dysfunction liver functions. Before initiating therapy, liver function tests should be performed in all patients, and therapy cannot be initiated if the level of liver enzymes ALT and/or AST is more than 3 times the upper limit of normal. Caution should be exercised when prescribing Valdoxan® to patients with initially elevated transaminase activity (above the upper limit of normal, but not more than 3 times the upper limit of normal).

Frequency of liver function tests

Before starting therapy, and beyond:

in approximately 3 weeks,
after approximately 6 weeks (end of the stopping period of therapy),
after approximately 12 and 24 weeks (end of the maintenance period of therapy) in the future - in accordance with the clinical situation.

When increasing the dose, liver function should be monitored at the same frequency as at the beginning of therapy. If the activity of transaminases in the blood serum increases, a repeat test should be performed within 48 hours.

During treatment

Treatment with Valdoxan® should be stopped immediately if:

the appearance of symptoms and signs of possible liver dysfunction (such as dark urine, discolored stools, yellow skin/eyes, pain in the right upper abdomen, new persistent and unexplained fatigue);
an increase in transaminase levels by more than 3 times, but compared with the upper limit of normal.

After discontinuation of therapy with Valdoxan®, liver function tests should be performed regularly until transaminase levels normalize.

Elderly patients

The effectiveness of the drug in elderly patients (aged 75 years and older) has not been established. In this regard, Valdoxan® should not be prescribed to patients in this age group.

Elderly patients with dementia

Valdoxan® should not be prescribed for the treatment of major depressive episodes in elderly patients with dementia (due to the lack of data on the effectiveness and safety of the drug in this group of patients).

Patients with kidney failure

In patients with severe renal failure, no significant changes in pharmacokinetic parameters were observed. However, experience with the use of Valdoxan® for major depressive episodes in patients with moderate to severe renal failure is limited. When prescribing Valdoxan® to such patients, caution should be exercised.

Bipolar disorders/mania/hypomania

Caution should be exercised when using Valdoxan® in patients with a history of bipolar disorders, manic or hypomanic episodes. If symptoms of mania appear, you should stop taking the drug.

Suicide/suicidal behavior

People who are depressed have an increased risk of suicidal ideation, self-harm, and suicide (suicide-related events). The risk remains until a clear remission occurs. Patients should be under medical supervision until the condition improves (after starting therapy, it may take several weeks for the condition to improve). Clinical experience suggests that the risk of suicide may increase in the early stages of remission.

Patients with a history of events associated with suicide, as well as patients who had suicidal intentions before starting therapy, are at risk and should be under close medical supervision during therapy.

The results of a meta-analysis of clinical trials of antidepressants in patients with mental disorders indicate an increased risk of suicidal behavior in patients under the age of 25 years while taking antidepressants compared with placebo. During the treatment period, patients, especially those at risk, should be under close medical supervision, especially at the beginning of therapy and when changing the dose of the drug. Patients (and their caregivers) should be advised to seek immediate medical attention if their condition worsens, if they experience suicidal or unusual behavior, or if they experience suicidal thoughts.

Combined use with inhibitors of the CYPIA2 isoenzyme

Caution should be exercised when using agomelatine simultaneously with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin) due to the possibility of increasing the concentration of agomelatine.

Patients with lactose intolerance

The drug should not be used in patients with lactose intolerance: lactase deficiency, galactosemia and glucose-galactose malabsorption.

Impact on the ability to drive vehicles and operate machinery

No studies have been conducted to study the effect of Valdoxan® on the ability to drive a car or use other mechanisms. It should be remembered that dizziness and drowsiness are common side effects of agomelatine.

Overdose

Studies on healthy volunteers have shown that when taken orally, agomelatine is well tolerated at doses up to 800 mg/day. Cases of agomelatine overdose are rare. During clinical trials, doses of up to 300 and up to 375 mg/day were reported in combination with other psychotropic drugs. In all of these cases, no signs or symptoms of overdose were reported.

Treatment: In case of overdose, specific antidotes for agomelatine are not known. Symptomatic therapy and the usual monitoring for such cases in specialized departments are indicated.

Side effects Valdoxan 25 mg 28 pcs. film-coated tablets

"Valdoxan" can cause adverse reactions from:

central and peripheral nervous system: dizziness, paresthesia;
Gastrointestinal tract: nausea, diarrhea, dry mouth, pain in the epigastric zone, AST increase 3 times relative to normal;
skin: dermatitis, itching, eczema, erythematous rash;
eye: blurred vision.

Drug interactions

Potentially possible interaction: 90% of agomelatine is metabolized in the liver with the participation of CYP1A2 isoenzymes and 10% with the participation of CYP2C9/19. Therefore, any drugs whose metabolism depends on these isoenzymes may increase or decrease the bioavailability of agomelatine. Fluvoxamine, which is a strong inhibitor of CYP1A2 and 2C9, may significantly slow down the metabolism of agomelatine (simultaneous use is not recommended).

Paroxetine (a CYP1A2 inhibitor) and fluconazole (a strong CYP2C9 inhibitor) do not interfere with the pharmacokinetics of agomelatine. Estrogens, which are moderate inhibitors of CYP1A2, have been shown to enhance the effects of agomelatine. As long as the therapeutic concentration of the drug remains within the normal range of pharmacokinetics, no dose adjustment is required.

Smoking increases the effect of CYP1A2, but has been shown to only slightly decrease the duration of action of agomelatine. Therefore, smokers do not need to adjust their dose.

Possibility of action of agomelatine on other drugs Agomelatine does not induce or inhibit CYP450 isoenzymes and therefore does not affect the action of drugs whose metabolism is associated with these isoenzymes. In healthy volunteers, agomelatine did not change the pharmacokinetics of theophylline (CYP1A2). Agomelatine does not change the free concentration of drugs that are significantly bound to plasma proteins and, in turn, do not affect the concentration of agomelatine.

There is no pharmacokinetic or pharmacodynamic interaction between lorazepam and agomelatine. There is no pharmacokinetic or pharmacodynamic interaction between lithium preparations and agomelatine. There are no data on the use of agomelatine concomitantly with electroconvulsive therapy. Since agomelatine did not show seizure-predisposing properties in animal experiments, undesirable effects of electroconvulsive therapy when used together seem unlikely.

Side effects

As a rule, the manifestation of side effects is observed at the very beginning of treatment. Patients are especially often concerned about: nausea, dizziness, drowsiness, headache, insomnia, fatigue, anxiety, sweating, and so on. All these symptoms are not severe and usually do not require additional treatment. Gradually their manifestation decreases and completely disappears.

Instructions for Valdoxan (Method and dosage)

The tablets are intended to be taken orally, regardless of food, whole - without crushing or chewing. If the next dose of the drug was missed, then no additional medication is required, and the next tablet is taken as usual.

At the same time, the instructions for use of Valdoxan indicate that you need to take 25 mg or 1 tablet daily. If there is no improvement within 2 weeks, it is possible to increase the dosage as prescribed by the doctor.

During treatment, it is necessary to monitor liver function at the initial stage, then periodically throughout therapy. The average treatment course is 6 months or until the unwanted symptoms completely disappear.

Valdoxan®

Liver function monitoring

Cases of liver damage (including liver failure, increases in liver enzyme levels more than 10 times the ULN, hepatitis and jaundice) have been reported in patients taking Valdoxan® in the post-marketing period. Most of these disorders occurred in the first months of treatment. The nature of liver damage appears to be primarily hepatocellular. As a rule, after cessation of therapy, transaminase levels returned to normal values.

It is recommended to monitor liver function at the beginning of therapy and then periodically, after 3 weeks, after 6 weeks (end of the relief period of therapy), 12 weeks and 24 weeks (end of the maintenance period of therapy) after the start of therapy, and thereafter in accordance with the clinical situation. When increasing the dose, liver function should be monitored at the same frequency as at the beginning of the drug.

If the activity of transaminases in the blood serum increases, a repeat test should be performed within 48 hours. If the activity of transaminases is more than 3 times higher than the ULN, the drug should be discontinued. In the future, the functional state of the liver should be regularly monitored until transaminase activity normalizes.

If you experience symptoms and signs of possible liver dysfunction (such as dark urine, discolored stools, yellow skin/eyes, pain in the right upper abdomen, new persistent and unexplained fatigue), Valdoxan should be stopped immediately.

Caution should be exercised when prescribing Valdoxan® to patients with elevated transaminase activity before starting therapy (above the ULN, but not more than 3 times the ULN).

Caution should be exercised when prescribing Valdoxan® to patients with risk factors for developing liver dysfunction, such as obesity/overweight/non-alcoholic fatty liver disease, diabetes mellitus, drinking significant amounts of alcohol, or taking medications that can cause liver dysfunction.

Elderly patients

The effectiveness of the drug in elderly patients (aged 65 years and older) has not been established. There is limited data on the use of Valdoxan® for major depressive episodes in patients aged 65 years and older. When prescribing the drug to elderly patients, caution should be exercised.

Patients with kidney failure

In patients with severe renal failure, no significant changes in pharmacokinetic parameters were observed. However, experience with the use of the drug for major depressive episodes in patients with moderate or severe renal failure is limited. When prescribing Valdoxan® to such patients, caution should be exercised.

Bipolar disorders/mania/hypomania

Caution should be exercised when using Valdoxan® in patients with a history of bipolar disorders, manic or hypomanic episodes. If symptoms of mania appear, you should stop taking the drug.

Suicide/suicidal behavior

During the treatment period, patients, especially those at risk, should be under close medical supervision, especially at the beginning of therapy and when changing the dose of the drug. Patients (and their caregivers) should be advised to seek immediate medical attention if their condition worsens, if they experience suicidal or unusual behavior, or if they experience suicidal thoughts.

Combined use with CYP1A2 isoenzyme inhibitors

Caution should be exercised when using agomelatine simultaneously with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, grepafloxacin, enoxacin) due to the possibility of increasing the concentration of agomelatine.

Impact on the ability to drive vehicles and operate machinery

Overdose

In practical medicine, isolated cases of agomelatine . In this case, such undesirable symptoms arise as: drowsiness , stomach pain, restlessness, anxiety, weakness, tension, dizziness , and so on.

If the overdose is insignificant, then the condition will soon normalize on its own, without deviations in the activity of the cardiovascular and nervous systems, or disturbances in laboratory parameters.

If necessary, carry out symptomatic treatment and monitor the general condition of the patient.

Interaction

The simultaneous use of this drug and various isoenzyme inhibitors, for example, fluvoxamine, Ciprofloxacin , leads to a significant slowdown in the metabolism of agomelatine , and accordingly to an increase in its concentration. Therefore, simultaneous therapy with these drugs is contraindicated.

Also, Rifampicin , which takes part in the metabolism of agomelatine, can reduce its bioavailability. This can also occur in patients who abuse smoking. As for the potential effect of agomelatine on other types of drugs, it is insignificant or not fully studied.

Valdoxan tablet p/pl/o 25 mg N28 (Servier)

- Hypersensitivity to agomelatine and/or any of the excipients of the drug (see section “Composition”). - Liver failure (for example, cirrhosis or active liver disease) or an increase in transaminase levels more than 3 times the upper limit of normal (see sections “Dosage and Administration” and “Special Instructions”). - Concomitant use of potent inhibitors of the CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) (see section “Interaction with other drugs and other types of interactions”). — Children under 18 years of age (due to lack of sufficient experience in clinical use). In children and adolescents taking other antidepressants, suicidal behavior (suicide attempts and suicidal thoughts) and hostility (mainly aggressiveness, conflict behavior, irritation) were observed more often compared to the placebo group. The drug should not be used in patients with lactose intolerance: lactase deficiency, galactosemia and glucose-galactose malabsorption. PRECAUTIONS FOR ADMINISTRATION Patients with moderate to severe renal impairment in the treatment of major depressive episodes, while co-prescribing agomelatine with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin), patients with a history of manic or hypomanic episodes, patients with a history of events associated with suicide, as well as patients who had suicidal intentions before starting therapy. Caution should be exercised when prescribing the drug to patients who abuse alcohol or take drugs that can cause liver dysfunction. USE IN PREGNANCY AND BREASTFEEDING Pregnancy Data on the use of agomelatine during pregnancy are absent or limited (less than 300 pregnancy outcomes). Animal studies have not revealed direct or indirect harmful effects on pregnancy, embryonic and fetal development, labor and postnatal development. As a precaution, it is recommended to avoid prescribing Valdoxan during pregnancy. Breastfeeding It is not known whether agomelatine passes into breast milk in lactating women. In animal experiments, it was shown that agomelatine and its metabolites pass into breast milk. Risk to the newborn/child cannot be excluded. It is necessary to assess the importance of breastfeeding for the child and therapy for the mother and make a decision to stop breastfeeding or stop taking the drug. Fertility Reproduction studies in rats and rabbits have shown no effect of agomelatine on fertility.

Analogues of Valdoxan

Level 4 ATC code matches:
Pipofezin

Bethol

Incazan

Melitor

Azafen

Miaser

Velafax

Mirtazonal

Venlaxor

Remeron

Venlafaxine

Lerivon

Mirtazapine

Cymbalta

Velaxin

Coaxil

Pyrazidol

Deprim

Gelarium Hypericum

Negrustin

The main analogue is Agomelatine . There are also other analogues of Valdoxan, for example – Adaptol and Paxil .

Reviews about Valdoxan

This remedy is quite often used in clinical practice. At the same time, its mild but effective effect was noted. Some patients report that the treatment was quite successful, without unwanted symptoms or intolerance reactions.

However, there are also reviews of Valdoxan when patients were bothered by: a feeling of nausea , attacks of aggression , and a lack of appetite . Such symptoms persisted not only at the initial stage, so it was necessary to change the drug.

In any case, the choice of an antidepressant must be approached with special responsibility and only take drugs prescribed by a specialist in a certain dosage.

Experience of using alprazolam in complex therapy of mental disorders

Tranquilizers (benzodiazepines) constitute one of the main classes of psychotropic drugs and have been used in clinical medicine for more than 50 years.

Currently, about 30 different drugs of benzodiazepine structure (anxiolytics and hypnotics) are used. Despite the fact that in 1983 the WHO recognized the ability of benzodiazepines to cause drug dependence, they are still widely used not only in psychiatry, but also in other areas of medicine, and in a number of cases they are irreplaceable. The development of antidepressants with a pronounced anxiolytic effect (especially selective serotonin reuptake inhibitors), anxiolytics and hypnotics of non-benzodiazepine structure contributed to some displacement of benzodiazepines from medical practice, however, due to a specific mechanism of action that ensures high and rapidly developing psychotropic activity and good tolerability, they invariably occupy their niche in the treatment of mental disorders of the neurotic level.

In the spectrum of action of benzodiazepines, several main effects are traditionally distinguished: anxiolytic (anti-anxiety), sedative, hypnotic, muscle relaxant, anticonvulsant and amnestic. Currently, their anxiolytic and hypnotic effects are most important for clinical practice, while the rest are almost not used or are considered as side effects [10].

Alprazolam, a typical representative of benzodiazepine anxiolytics, has all the properties of drugs in this group to varying degrees.

The main thing for it is an anxiolytic effect. Alprazolam is a high-potency benzodiazepine, that is, a pronounced anxiolytic effect develops when using low doses of the drug. This is explained by the fact that alprazolam has a higher affinity for specific benzodiazepine receptors [1].

There are other properties that distinguish alprazolam from other representatives of this group: average duration of action, less pronounced sedation and behavioral toxicity. These features allow alprazolam to be widely used, including in outpatient practice. In addition, the ability of alprazolam to reduce the symptoms of depression is used in the treatment of mental disorders. Alprazolam is believed to be the only benzodiazepine tranquilizer that exhibits antidepressant activity [44].

The spectrum of clinical effects of alprazolam, like other benzodiazepines, is based on the modulation of GABAA receptors, followed by secondary neurochemical and hormonal changes. It is discussed that stimulation of GABA receptors leads to changes in the activity of the monoaminergic system [10]. At the same time, a weakening of the activity of the hypothalamic-pituitary-adrenal system is described [57]. Long-term use of benzodiazepines, including alprazolam, leads to a decrease in the sensitivity of GABA receptors [34]. This is the basis for the development of the phenomenon of addiction. However, it is believed that tolerance does not develop to all effects of benzodiazepines. It is unconditional regarding its hypnotic, muscle relaxant and anticonvulsant effects and is controversial regarding its anxiolytic effect [10]. Indeed, many patients take alprazolam long-term to relieve anxiety without reducing the effectiveness of treatment.

It is assumed that due to the selective effect on the α2 and α3 subunits of GABA receptors, the antidepressant effect of alprazolam is realized, which is absent in the spectrum of psychotropic activity of other tranquilizers, the action of which is associated with stimulation of GABA receptors [44].

There are interesting data on the bipolarity of the neurochemical action of alprazolam depending on the initial emotional state: in depression, the drug enhances noradrenergic activity (especially in the prefrontal cortex and hippocampus), and in anxiety it weakens it [46].

Benzodiazepines do not have an affinity for dopamine, serotonin, cholinergic, adrenergic, histamine and other receptors of the central nervous system and the autonomic nervous system. This determines the absence of side effects during their use, which are so characteristic of other classes of psychotropic drugs.

The average time to reach the maximum concentration of alprazolam in the blood is 1.5 hours [35, 36]. Due to its high lipophilicity, the drug, like other benzodiazepines, penetrates well through the blood-brain barrier, which explains the rapid onset of its therapeutic effect. Alprazolam is an intermediate-acting benzodiazepine: the average half-life of the drug is 11 hours [19].

According to various literature sources, alprazolam has a unique spectrum of psychotropic activity compared to other tranquilizers [2, 11]. The drug is most effective in the treatment of disorders, the clinical picture of which is mainly determined by anxiety symptoms of varying degrees of severity. Such conditions include, first of all, panic disorder, generalized anxiety disorder, various anxiety-depressive states, including reactive and somatogenic. In addition, alprazolam has proven itself in the treatment of obsessive-compulsive disorder, isolated phobias, and withdrawal states.

The effectiveness of alprazolam in the treatment of panic disorder is evidenced by the results of numerous comparative studies [45]. A number of studies [11] indicate that in the treatment of panic disorder, compared with other benzodiazepine tranquilizers, alprazolam significantly reduces the frequency of panic attacks and reduces the severity of anxiety and depressive symptoms. If cases of partial improvement are taken into account, alprazolam is effective in 80% of cases [9, 15]. It is believed that in this regard the effect of alprazolam is comparable only to clonazepam [7,11]. It has been established that alprazolam at an average dose of 4 to 7 mg/day. more effective than placebo during 4 weeks of observation [12]. However, there was no direct relationship between the concentration of the drug in the blood and the effectiveness of therapy. This means that the effectiveness of treatment largely depends not on the dose of the drug, but on clinical and psychopathological factors. In addition, it is indicated that the drug acts not only on anticipatory anxiety, but also on the symptoms of panic attacks themselves, reducing their severity and preventing the development of repeated panic attacks [6]. The dose range of alprazolam for the treatment of panic disorder is wider than for the treatment of other anxiety conditions, and is up to 10 mg/day. (on average 2-6 mg/day) [1.47], divided into 3-4 doses.

Numerous studies have examined the use of alprazolam for generalized anxiety disorder (GAD). The symptoms of GAD are effectively reduced by treatment with alprazolam at an average daily dosage of 0.5-4.0 mg, divided into 3-4 doses, in different age groups of patients, which is confirmed by the results of numerous placebo-controlled studies [14, 24, 25, 26, 29 ]. It has been established that, compared with other benzodiazepine tranquilizers, the use of alprazolam is accompanied by fewer side effects [6, 14, 27, 32]. It should also be noted that the effect is relatively rapid, manifesting itself already during the first week of treatment [33]. Despite the high effectiveness of alprazolam in the treatment of GAD, antidepressants are currently preferred in the treatment of this pathology [3, 48, 49]. However, even in this case, the role of benzodiazepines in the treatment of GAD cannot be underestimated. Considering the fact that the effect of antidepressants appears only several weeks after the start of therapy, the use of benzodiazepines at the beginning of treatment to relieve anxiety and insomnia does not yet have an alternative. Due to the risk of developing drug dependence, it is recommended to use alprazolam for several weeks followed by gradual withdrawal. In cases where this period is not enough to develop a lasting therapeutic effect, longer use of the drug is possible, subject to careful follow-up.

In a study of the effectiveness of alprazolam in patients with GAD manifested by irritable bowel syndrome, after 4 weeks of therapy there was a significant reduction in both anxiety symptoms (in 98% of patients) and gastrointestinal complaints (in 89% of patients) [58]. The drug has also proven itself in the treatment of anxiety in alcohol withdrawal states [40].

It is repeatedly mentioned in the literature that, in addition to the anxiolytic effect itself, the drug also has an antidepressant effect, which has not been detected in other tranquilizers [6, 17, 41,60]. Its presence was discovered shortly after the active introduction of alprazolam into clinical practice and was confirmed in a number of further studies. There are indications of the effectiveness of alprazolam not only in neurotic, but also in endogenous depression [6]. Moreover, its effect is comparable to tricyclic antidepressants [17, 39, 53, 55]. Many authors indicate the preference of its use for syndromes in the structure of which there is a combination of anxiety and depressive symptoms [4, 5,10].

There is evidence indicating the effectiveness of alprazolam in the treatment of premenstrual syndrome [30, 37].

The successful use of alprazolam in the treatment of acute stress and obsessive-compulsive disorders has been described. In this case, the drug was prescribed either at the beginning of the course in addition to selective serotonin reuptake inhibitors (SSRIs) to relieve severe anxiety, or as monotherapy in cases of resistance or intolerance to SSRIs [16, 42]. However, despite speculation, alprazolam was ineffective in the treatment of post-traumatic stress disorder (PTSD) [23].

Data have been obtained on the use of alprazolam as a corrector of extrapyramidal symptoms (especially acute dystonia and akathisia) caused by taking antipsychotics [38]. However, in the presence of other highly effective means of correcting neuroleptic syndrome, alprazolam cannot be considered as a first-line drug.

The most common side effects during therapy with alprazolam are sedation and drowsiness [31], which is explained by the interaction of the drug with GAMKA receptors and during the course of treatment the above side effects decrease significantly.

Regular use of alprazolam should be discontinued gradually to avoid the development of withdrawal syndrome. During this period, lasting from several weeks to months, the daily dosage of the drug is gradually reduced until complete discontinuation [54]. A number of studies [43, 48, 54] note that reducing the dose of benzodiazepine tranquilizers may be accompanied by withdrawal syndrome and the return of clinical manifestations of the underlying disease, especially in cases of abrupt cessation of therapy.

Despite the widespread perception of the risk of drug dependence, data from numerous studies indicate that the incidence of dependence among patients receiving alprazolam is relatively low [50, 51, 52]. The authors note that dependence on benzodiazepines is a relatively rare phenomenon and occurs mainly in individuals who abuse alcohol or drugs.

There are some other side effects of alprazolam worth mentioning. A number of studies have revealed a deterioration in the processes of perception and reproduction of new information [28, 56]. This feature must be taken into account when driving a car [18]. It is also important to note the interaction of alprazolam with alcohol, because Many patients with anxiety symptoms independently resort to drinking alcohol to alleviate their condition. Their combined use leads to a significant deterioration in results when performing psychological tests [20], and in some patients it increases aggression and irritability [21,22].

Thus, as numerous data show, including recent years, alprazolam remains a fairly popular and effective tranquilizer. However, many issues require clarification and additional study. In particular, the place of alprazolam in the complex treatment of mental disorders along with new drugs from other psychopharmacological groups needs to be considered. Questions remain not entirely clear regarding the dosages of alprazolam used, the possible duration of its use, as well as the frequency and conditions for the formation of dependence.

Purpose of the study: to analyze the use of alprazolam in the complex treatment of various mental disorders to clarify the indications for its use.

The medical histories of 124 patients who were undergoing inpatient (58 people - 46.8%) and outpatient (66 people - 53.2%) treatment in the psychiatric clinic named after. S.S. Korsakov First Moscow State Medical University named after. THEM. Sechenov and taking alprazolam at a certain stage of therapy. All patients underwent a thorough psychiatric and somato-neurological examination using the necessary paraclinical methods to assess the effectiveness of therapy and possible side effects.

Among the patients there were 74 women (59.7%) and 50 (40.3%) men aged from 26 to 70 years. The duration of the diseases ranged from 2 months to 40 years.

According to the results of the assessment of mental disorders according to ICD-10, patients were distributed as follows: schizophrenia F20 was diagnosed in 24 patients (19.4%), of which paranoid F20.0 - in 10 (8.1%), sluggish F21 - in 14 (11.3 %); affective disorders F3 - in 46 (37.2%), including a depressive episode of varying severity F32 - in 8 (6.5%), recurrent depressive disorder F33 - in 26 (21.0%), bipolar disorder F31 - in 12 (9.7%); organic brain lesions F06 - in 6 (4.8%), of which organic anxiety disorder F06.4 - in 4 (6.4%), organic personality disorder F07.0 - in 2 (1.6%); psychogenic disorders F4 - in 48 (38.7%), including panic disorder F41.0 - in 16 (12.9%), generalized anxiety disorder F41.1 - in 4 (3.2%), obsessive-compulsive disorder F42.2 - in 2 (1.6%), adaptation disorders in the form of depressive F43.21 and anxiety-depressive reaction F43.22 - in 26 (21.0%).

All patients received treatment with psychotropic drugs of various pharmacological groups in accordance with the leading psychopathological syndrome. As part of complex therapy, all patients were prescribed alprazolam as a main or auxiliary agent in a daily dose of 0.5 to 1.5 mg in 2-3 doses [1]. About half of the patients are 59 people. (47.6%) fell ill for the first time: they were diagnosed with a first-time depressive episode (8), adaptation disorders (26), neurotic anxiety-phobic disorders (14), organic disorders (4), low-grade schizophrenia (5) and paranoid schizophrenia (2 ). Before entering the clinic, these patients practically did not receive (with the exception of some recommendations from neurologists) psychotropic drugs, including tranquilizers. The remaining patients had previously taken various drugs, including benzodiazepines, but none of the patients had symptoms of established drug dependence at the time of their visit to the clinic.

When prescribing alprazolam, primarily its anxiolytic and antidepressant effects were taken into account. Weak sedative, hypnotic, muscle relaxant and amnestic effects, especially in small doses, made it possible to use it as a daytime tranquilizer in outpatients, including workers.

As is known, one of the main indications for the use of alprazolam is generalized anxiety disorder (GAD), but the diagnostic criteria for GAD are still controversial [3], and anxiety is often present in other forms of neuroses and depression. In our study, there were few patients with this diagnosis, and all of them took alprazolam in combination with SSRI antidepressants, mainly paroxetine. The anti-anxiety effect of these antidepressants is comparable to alprazolam [48], but it appears several weeks after the start of therapy. In the first weeks of treatment, anxiety may increase and sleep may be disrupted. It is during this period that the prescription of tranquilizers, and in particular alprazolam, has no alternative. The duration of treatment in patients with GAD is from two weeks to two months at an average dose of 0.75 mg per day (0.25 mg 3 times a day).

When treating patients with panic disorder, doses of up to 1 mg per day were used in 3-4 doses. The duration of therapy ranged from 3 to 8 months. Observation of patients over time shows that at first panic attacks disappear quite quickly, then the anxious anticipation of an attack gradually reduces, fears decrease and, accordingly, avoidant behavior disappears. In some cases, in the presence of symptoms of depression and in order to prevent panic attacks, antidepressants from the SSRI group, in particular Cipralex, were additionally prescribed.

For obsessive-compulsive disorder, alprazolam (dose 0.5 mg per day) was used in one case in combination with fluoxetine for 1 month, then due to insufficient effectiveness, therapy was changed. In another case, in a patient with various obsessions (fears, ideas, compulsions) in combination with panic attacks and avoidant behavior, alprazolam at a dose of up to 1.5 mg per day in combination with etaprazine up to 8 mg per day was successfully used for a long time (more 4 years) with almost complete reduction of symptoms and restoration of social functioning, in the absence of symptoms of addiction.

Patients with depressive disorders, including endogenous and neurotic depression, in our study made up more than half of all observations - 58.2%. In most cases, the structure of the depressive syndrome included symptoms of anxiety, which was an indication for the prescription of apprazolam, especially in the first weeks of therapy, before the onset of the anxiolytic effect of antidepressants. For primary depressive episodes and recurrent depression, alprazolam was used mainly as part of complex therapy along with antidepressants of various generations (maprotiline, azaphene, paroxetine, mirtazapine, Cymbalta, Valdoxan, etc.), and small doses of some antipsychotics (sulpiride). In some cases, hypnotics (zopiclone) were additionally prescribed for sleep disturbances. Treatment of depression in the context of bipolar disorder (BD) had its own characteristics, taking into account the possibility of transition to the manic phase, especially with BD-1. Antidepressants that do not cause an inversion of affect were used (azafen, valdoxan, fevarin). Already during the relief therapy, anticonvulsants (vaporates, carbamazepine) and antipsychotics (quetiapine, olanzapine) were prescribed, which the patients continued to take during the period of remission as maintenance therapy. In bipolar disorder-11, depressive symptoms were treated with antidepressants from the SSRI group, venlafaxine, valdoxan in combination with alprazolam, which has an anxiolytic effect, especially in the first weeks of therapy before the development of the antidepressants’ own effects, and potentiates their antidepressant activity [5]. Among anticonvulsants, preference was given to lamotrigine and valproic acid preparations, and among antipsychotics, preference was given to quetiapine. In almost half of the cases of neurotic depression (12 people), alprazolam was used as monotherapy, at a dose of 0.75-1 mg for 4-7 weeks with a good effect, i.e. almost complete recovery.

This once again indicates that alprazolam has an antidepressant effect.

Many patients with depression experienced symptoms of somatic anxiety (including somatized depression), which disappeared along with mental anxiety. Perhaps in this case we can talk about the vegetotropic effect of alprazolam, like other benzodiazepines (phenazepam, diazepam). Another explanation is possible: along with anxiety, its somato-vegetative “accompaniment” also goes away.

In the history of many patients with panic disorder, anxiety-phobic disorders, and recurrent depression, there were episodes of effective use of alprazolam with tianeptine with a fairly rapid reduction of symptoms and restoration of social functioning.

For organic brain lesions, alprazolam was used as an anti-anxiety and sedative in combination with small doses of sedative antipsychotics (clozapine, olanzapine), nootropics. The duration of therapy is no more than a month, daily doses are up to 0.75 mg. Antipsychotics in these cases were prescribed as behavior correctors, and alprazolam “mitigated” the side effects.

In case of sluggish schizophrenia, alprazolam was prescribed as part of a polymorphic neurosis-like syndrome, which included anxiety-phobic, panic, obsessive-compulsive and depressive disorders. As a rule, it was used in combination with antidepressants (rexetine, mirtazapine, amitriptyline), antipsychotics (sulpiride, sonapax, chlorprothixene, quetiapine), hypnotics (zopiclone, zolpidem), short courses from two to four weeks at a dose of 0.5-0. 75 mg per day.

A special group consisted of patients with paranoid schizophrenia, to whom alprazolam was prescribed in addition to antipsychotics (clozapine, olanzapine, paliperidone, risperidone) as an anti-anxiety agent and potentiating sedative effect. This made it possible to reduce doses of antipsychotics, which is especially important when conducting treatment on an outpatient basis in order to improve social adaptation and quality of life. Courses of therapy of varying durations, from two weeks to several months, depending on the indications, the dose of the drug is 1-1.5 mg per day.

Thus, the study confirmed that alprazolam has high anxiolytic activity even in small doses with insignificant sedative and hypnotic effects, which allows its use as a daytime tranquilizer and anxiolytic in patients with a wide range of anxiety-phobic and panic disorders of various origins. Alprazolam differs favorably from other benzodiazepines by having an antidepressant effect, so it can be used to treat not only anxiety, but also depressive disorders. There is good tolerability and high safety of the drug, as well as a virtual absence of the risk of drug dependence when using small doses and strictly observing the indications for use. Alprazolam can be prescribed in inpatient and outpatient settings, both in short courses and long-term, depending on the nature of mental disorders.

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Experience of alprazolam usage in a complex therapy of psychiatric disorders.

NA Tuvina, DS Danilov, VV Balabanova, SV Prochorova, IG Korobkova

Department of Psychiatry and Addiction

IM Sechenov First Moscow State Medical University

SUMMARY : Literary data, defining the peculiarities of alprazolam action, its psychotropic effects, tolerability, the possibility of its usage in various psychiatric disorders proven by numerous studies, were analyzed. Our own experience of alprazolam use, mainly in combination with drugs of other psychopharmacological groups [antidepressants, neuroleptics, anticonvulsants] in the treatment of psychiatric disorders: depressions of various genesis, disorders of anxiety and phobic spectrum, obsessions were represented. 124 psychiatric in- and outpatients showed high efficacy and good tolerability of small daily doses of alprazolam and the absence of dependence and withdrawal syndrome.

KEY-WORDS : alprazolam, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, acute stress disorder, schizophrenia, affective disorder.

CONTACT : NA Tuvina ( [email protected] ].

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