The relevance of studying late-life depression is primarily due to the high frequency of this pathology in older age groups of the population. According to various authors [1–3], 10 to 25% of elderly people suffer from depression, and depression in older people is often not recognized by doctors, which leads to prolongation and chronicity of the disease [1, 3, 4].
Most researchers agree that the prevalence rates of depressive disorders among older age groups are almost 2 times higher than the corresponding estimates for younger populations. Depression increases the risk of hospitalization in older people, leads to an increase in the length of their hospital stay for somatic diseases, causes a worse therapeutic response to medications, is one of the most important causes of suicide, and increases the risk of developing dementia. According to WHO experts, by 2021 depression will become the leading disease in terms of costs of care for patients in older age groups of the population. If we take into account that at a later age there is an increased risk of unwanted side effects and complications of psychopharmacotherapy associated with age-related characteristics of the processes of biotransformation and elimination of drugs, as well as the burden of elderly patients with comorbid somatic and neurological diseases requiring constant treatment, then this makes it understandable why treatment of late-life depression is a particularly difficult problem in modern psychiatry. In this regard, increasing the effectiveness and safety of psychopharmacotherapy in the treatment of elderly and senile patients with depressive disorders becomes highly relevant.
In recent years, it has been established that the pathogenetic mechanisms of depression are associated not only with disorders of monoaminergic synaptic transmission and dysfunction of neuroendocrine systems, but also with disorders of the circadian system, characterized by disorganization of the endogenous (internal) rhythms of the body [5]. To date, one of the concepts of the pathogenesis of depressive disorders is chronobiological, based on the fact that depressive states are often accompanied by desynchronization of biological rhythms, primarily circadian (circadian), corresponding to daily fluctuations, i.e., a 24-hour period.
Disturbances in circadian rhythms can alter a variety of biological processes, such as the sleep-wake cycle, hormone release, body temperature (flattening diurnal temperature fluctuations), and other important physical functions. A study of pathophysiological indicators in depression, reflecting disturbances in the sleep-wake circadian rhythm, showed the presence of a number of biochemical abnormalities. Among them are a decrease in the nighttime concentration of melatonin in the blood plasma, a violation of the periodicity of fluctuations in the concentrations of prolactin, cortisol, thyroid-stimulating hormone, etc. [6].
Within the chronobiological concept of depression, a large place is given to sleep disorders. Some researchers consider early detection and treatment of sleep disorders as a way to prevent recurrent depression [7], as well as predict relapse of the disease [8]. This is confirmed by data from epidemiological studies indicating that more than 80% of adults suffering from depression have sleep disorders [9]. In older adults, insomnia is the most common complaint [10], and its frequency increases with increasing age [11].
Some authors [12] consider circadian rhythm disturbances and depressive disorders as two interrelated changes characteristic of old age. Restoration of circadian rhythms leads to normalization of sleep structure: in patients with depression, the duration of the slow-wave sleep phase increases without changing its total duration and the number of REM sleep phases, the severity of depressive symptoms changes during the day, which leads to the leveling of affective disorder [13]. In this regard, new antidepressants that are effective against insomnia and do not cause daytime sleepiness may represent a treatment for late-life depression. Such antidepressants include Valdoxan [14]. The first experience of using this drug in the treatment of depressive disorders in outpatient gerontopsychiatric practice turned out to be very positive [15].
Valdoxan is an agonist of MT1 and MT2 melatonin receptors and an antagonist of 5-HT2C serotonin receptors [16]. At the same time, Valdoxan does not show significant affinity for histaminergic, beta- and alpha-adrenergic, cholinergic, benzodiazepine and dopaminergic receptors, and does not affect the uptake of monoamines. Restoring the synchronization of circadian rhythms when taking Valdoxan is carried out by stimulating the receptors of melatonin, a hormone that plays a major role in synchronizing the body's circadian rhythms, including the sleep-wake cycle. According to V. Audinot et al. [16], the drug does not have a negative effect on memory and attention and has no behavioral toxicity. The use of Valdoxan has no effect on blood pressure and heart rate, and does not cause addiction or withdrawal syndromes (even with abrupt withdrawal).
The purpose of this study was to evaluate the therapeutic efficacy, tolerability and safety of Valdoxan in the treatment of depression in elderly psychiatric patients.
pharmachologic effect
Pharmacodynamics
Antidepressant, agonist of melatonergic MT1 and MT2 receptors and antagonist of serotonin 5-HT2c receptors.
Agomelatine is active in validated models of depression (learned helplessness test, despair test, moderate chronic stress), as well as in models with desynchronization of circadian rhythms, as well as in experimental situations of anxiety and stress. It has been shown that agomelatine does not affect the uptake of monoamines and has no affinity for α-, β-adrenergic receptors, histaminergic receptors, cholinergic, dopaminergic and benzodiazepine receptors.
Agomelatine enhances the release of dopamine and norepinephrine, especially in the prefrontal cortex and does not affect the concentration of extracellular serotonin. In animal experiments with circadian rhythm desynchronization, agomelatine has been shown to restore circadian rhythm synchronization through stimulation of melatonin receptors.
Agomelatine helps restore normal sleep structure, reduce body temperature and release melatonin.
The effectiveness of short-term use of agomelatine (therapy for 6-8 weeks) in doses of 25-50 mg in patients with major depressive episodes has been shown.
Agomelatine has also been shown to be effective in patients with more severe forms of depressive disorder (Hamilton scale score ≥25).
Agomelatine was also effective for initially high levels of anxiety, as well as for combined anxiety and depressive disorders.
The supporting antidepressant effect of agomelatine was confirmed (with a study duration of 6 months) at a dose of 25-50 mg 1 time/day. The results of the study confirmed the anti-relapse effectiveness of agomelatine, which was assessed by the time until the onset of disease relapse (p=0.0001). The relapse rate in the group of patients taking agomelatine was 22%, in the placebo group - 47%.
Agomelatine was shown to be effective in 6 of 7 clinical studies (benefit (2 studies) or comparable efficacy (4 studies)) in heterogeneous populations of adult patients with depression compared with selective serotonin reuptake inhibitors (SSRIs)/selective norepinephrine reuptake inhibitors (SNRIs). ) (sertraline, escitalopram, fluoxetine, venlafaxine or duloxetine). Antidepressant effect was assessed using the Hamilton scale (17-item version) as either a primary or secondary endpoint.
Agomelatine does not have a negative effect on alertness and memory; in patients with depression, agomelatine at a dose of 25 mg increases the duration of the slow-wave sleep phase without changing the number and duration of REM sleep phases. Taking agomelatine at a dose of 25 mg also promotes a faster onset of sleep with a decrease in heart rate and improved sleep quality (starting from the first week of treatment); however, there is no inhibition during the daytime.
When taking agomelatine, there was a tendency to reduce the frequency of sexual dysfunction (impact on arousal and orgasm).
Taking agomelatine has no effect on heart rate and blood pressure, does not cause sexual dysfunction, does not cause withdrawal syndrome (even with abrupt cessation of treatment) and addiction syndrome.
The effectiveness of agomelatine at a dose of 25-50 mg 1 time / day was confirmed in elderly patients (younger than 75 years) with depression during an 8-week clinical trial. There is no evidence of a significant effect in patients aged 75 years and older. The tolerability of agomelatine in elderly patients is comparable to that in young patients.
In a 3-week controlled trial of patients with major depressive disorder who were not responding to paroxetine (SSRI) or venlafaxine (SNRI), withdrawal syndrome was observed when switching from these antidepressants to agomelatine. Withdrawal syndrome appeared both after immediate cessation of treatment with previously prescribed SSRIs/SNRIs, and during their gradual withdrawal, which could be mistakenly taken as a manifestation of the low effectiveness of agomelatine at the initial stage of treatment.
The number of patients experiencing at least one withdrawal symptom 1 week after SSRI/SNRI discontinuation was lower in the long-dose taper group (gradually tapering the SSRI/SNRI dose over 2 weeks) than in the rapid taper group. dose (gradual reduction of SSRI/SNRI dose over 1 week), and than with immediate withdrawal: 56.1%, 62.6% and 79.8% of patients, respectively.
Functional disorders of the gastrointestinal tract (GIT) constitute a group of heterogeneous conditions. Such disorders can occur in any part of the gastrointestinal tract, from the esophagus to the anal canal, and they are common to the population of most countries [1-3].
Irritable bowel syndrome (IBS) is also one of the disorders considered. It is manifested by pain or discomfort in the abdomen, changes in the frequency and consistency of stools, bloating, difficulty defecating, and an increase in the amount of mucus in the stool [5]. Personality characteristics play a major role in the development of IBS. These patients are characterized by hysterical, neurotic reactions, cancerophobia, obsessive fears, and depression [6, 7].
In gastroenterology, the most common two forms of depression are somatogenic and somatoform. Somatogenic depression occurs in severe acute and chronic somatic diseases. With somatoform depression, patients complain of pain, dysfunction of the gastrointestinal tract, but no objective somatic disease is detected [4]. A patient may, without realizing depression, be treated for a long time and to no avail by doctors of various specialties [8]. In this case, depression can be a trigger in the development of IBS [7]. No less significant in these cases is sleep disturbance [9]. Therefore, along with symptomatic therapy, there is a need to prescribe antidepressants [10].
Tricyclic antidepressants are most often used in medical practice, which, however, along with their high efficiency, can cause a large number of side effects [11]. The most promising group of antidepressants at present are agonists of melatonergic receptors types 1 and 2 (MT1, MT2) and antagonists of serotonergic (5-HT2C) receptors, of which Valdoxan (agomelatine) is a representative.
Valdoxan has advantages over other antidepressants because it has high antidepressant effectiveness; is able to restore sleep quality in the shortest possible time without changing daytime activity [12]. It is one of the few antidepressants actively and successfully used in somatic clinics.
The purpose of the study was to evaluate the effectiveness and safety of Valdoxan therapy at a dose of 25-50 mg in the treatment of mild to moderate depressive disorders in patients with IBS.
Material and methods
The sample included 28 patients aged 29 to 64 years undergoing outpatient treatment for IBS. Among the patients included in the study, females predominated.
The criteria for inclusion of patients in the study were the presence of a confirmed diagnosis of IBS, non-psychotic depression, and age over 18 years. Exclusion criteria were: other intestinal diseases, severe comorbidities, cancer, pregnancy and lactation, substance abuse, taking medications that cause sleep disturbances (for example, psychotropic drugs), alcoholism.
Patients underwent the following studies: sigmoidoscopy, ultrasound of the stomach and intestines, stool analysis for dysbacteriosis, scatological examination.
The Hamilton Inventory (HAM-A and HAM-D), the Clinical Global Impression (CGI) scale, and the Hospital Anxiety and Depression Questionnaire were used to assess mental status, and the Adverse Event Scale was used to assess adverse events. In addition, an ECG was recorded, blood pressure was monitored, and general and biochemical blood tests were performed.
Patients were prescribed drugs that normalize intestinal function, myotropic antispasmodics, antiflatulents, magnesium drugs, laxatives, prebiotics, opioid receptor antagonists, cytoprotectors, aluminum-containing antacids, enterosorbents.
Valdoxan was also included in the patients' treatment regimen. It was prescribed at a dose of 25 mg per day in the evening. The course of therapy was 2 months. The patients' condition, the severity of depression and sleep disorders were assessed before treatment, after the 1st week of therapy and 2 months after treatment.
Results and discussion
When assessing the patients' condition in accordance with the Hamilton scale, the average score for the severity of depressive disorders was 17.8 (from 7 to 23.4). In the affective sphere, the most frequently observed signs of depression were decreased mood, sleep disturbances, and increased fatigue. Decreased performance and activity were the most intense symptoms hindering the rehabilitation of patients. In addition to depressive symptoms, patients had a number of anxiety, hypochondriacal, and autonomic disorders, which aggravated their condition. When assessing the anxiety radical, 64.7% of patients showed mental anxiety with preoccupation, anticipation of the worst, and irritability. The most pronounced were anxiety and tension. Anxiety could be paroxysmal or constant.
With syndromic qualification, it was possible to distinguish depression-anxiety syndrome in 64% of cases, asthenovegetative syndrome - in 22%, and depression with sadness syndrome - in 14%.
Positive results in the patients’ condition were observed within 1 week after starting Valdoxan. There was a decrease in the manifestations of depression and anxiety: pronounced - in 7 patients, moderate - in 16, mild - in 5. After 2 months of therapy: a pronounced therapeutic effect was noted in all patients.
In addition to the effect on depression and anxiety, taking Valdoxan led to a decrease in somatic complaints. In addition, the patients recorded normalization of sleep (by the end of the 1st week of therapy), a decrease in the incidence of somatoform pain and its duration.
Valdoxan at a dose of 25 mg was effective in 27 patients, and only in 1 patient, who had no positive effect at the end of the 1st week of therapy, the daily dosage was increased to 50 mg.
After 2 months of therapy, the average total score on the Hamilton scale was 4.4, which corresponded to a reduction in depressive symptoms by 75.4% compared to the initial level. By the end of the 2nd month, it was noted that all 28 patients stopped complaining of loss of usual interests, depression, early awakenings, and daily mood swings. Along with depression, anxiety symptoms also regressed. The number of patients with complaints of internal trembling decreased by 52.9%. If anxiety and fear of death were detected in 64.7% of patients before treatment, then after 2 months of therapy these manifestations were not recorded in any patient.
As for side effects, during the observation of patients there were no cases of orthostatic hypotension, the appearance of arrhythmias and/or intracardiac blockades, or changes in heart rate. It should also be emphasized that Valdoxan in therapeutic doses (25-50 mg at night) did not affect the clinical effectiveness and safety of drugs used to treat IBS. Discontinuation of Valdoxan at the end of the study period was not accompanied by signs of withdrawal syndrome.
Thus, the study showed that Valdoxan at a dose of 25-50 mg per day is effective in the treatment of mild or moderate depressive disorders in patients with IBS. It reduces somatic complaints. The drug is safe in relation to hemodynamic parameters. Therapy with Valdoxan allows you to quickly reduce or stop pain. The study allows us to conclude that it is advisable to add antidepressants to standard therapy for patients with IBS, which is important for improving the health status and improving the quality of life of patients.
Pharmacokinetics
Suction
After oral administration, agomelatine is rapidly (≥80%) absorbed. Cmax in plasma is achieved 1-2 hours after oral administration. Absolute bioavailability after taking a therapeutic dose is low (<5%); interindividual variability is significant. Bioavailability is higher in women than in men. Bioavailability increases with oral contraceptives and decreases with smoking.
When the drug was prescribed in therapeutic doses, Cmax increased in proportion to the dose. When taken in higher doses, a more pronounced “first pass” effect through the liver was observed. Meal intake (both regular and high-fat) did not affect either bioavailability or extent of absorption. Interindividual variability increased when eating a high-fat diet.
Distribution
Vd in the equilibrium state was about 35 l. Plasma protein binding is 95%, regardless of drug concentration, age or the presence of renal failure.
In case of liver failure, a twofold increase in the free fraction of the drug was observed.
Metabolism
After oral administration, agomelatine undergoes rapid oxidation, mainly due to CYP1A2 and CYP2C9. The CYP2C19 isoenzyme is also involved in the metabolism of agomelatine, but its role is less significant.
The main metabolites in the form of hydroxylated and demethylated agomelatine are inactive, quickly bind and are excreted by the kidneys.
Removal
T1/2 from plasma is from 1 to 2 hours. Elimination occurs quickly. Metabolic clearance is about 1100 ml/min. Excretion occurs mainly by the kidneys (80%) 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
In patients with severe renal failure, a single dose of agomelatine at a dose of 25 mg did not significantly change the pharmacokinetic parameters. Due to limited clinical experience, caution should be exercised when prescribing agomelatine to patients with moderate to severe renal impairment.
When agomelatine was prescribed at a dose of 25 mg to patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) chronic liver failure against the background of liver cirrhosis, an increase in its plasma concentration by 70 and 140 times was noted , respectively, compared with volunteers matched for sex, age and smoking behavior, but without liver failure.
When agomelatine 25 mg was administered to elderly patients (65 years and older), it was noted that the mean AUC and mean Cmax were 4 times and 13 times higher, respectively, in patients aged 75 years and older compared with patients younger 75 years old. The total number of patients treated with the 50 mg dose was too low to draw any conclusions. No dose adjustment is required depending on age.
There are no data on racial differences in pharmacokinetic parameters.
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.
Contraindications
- liver failure (for example, cirrhosis or active liver disease) or an increase in transaminase levels by more than 3 times relative to ULN (see sections “Dosage regimen” and “Special instructions”);
- simultaneous use of powerful inhibitors of the CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) (see section “Drug 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;
- lactose intolerance (lactase deficiency, galactosemia and glucose-galactose malabsorption);
- hypersensitivity to agomelatine and/or any of the excipients of the drug (see section “Composition and release form”).
The drug should be prescribed with caution when treating major depressive episodes in patients with moderate to severe renal failure; when administering 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.
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] ].
Dosage
The drug is prescribed orally. Valdoxan can be taken with or without food. The tablets should be swallowed whole without chewing.
If you miss taking the next dose of the drug, during the next dose Valdoxan is taken at the usual dose (you should not take the missed dose of the drug).
To improve control over taking the drug, a calendar is printed on the blister containing the tablets.
The recommended dose is 25 mg (1 tablet) 1 time/day before bedtime. In the absence of clinical dynamics after two weeks of treatment, the dose can be increased to 50 mg (2 tablets of 25 mg each) 1 time/day before bedtime.
The decision to increase the dose should be made taking into account the increasing risk of increased transaminase activity. The dose should be increased to 50 mg after assessing the benefits and risks for the individual patient and under strict monitoring of liver function tests.
Before starting therapy, liver function tests should be performed in all patients. Therapy cannot be started in patients with transaminase levels more than 3 times the upper limit of normal (see sections “Contraindications” and “Special Instructions”). During treatment, liver function should be monitored periodically at approximately 3 weeks, approximately 6 weeks (end of the treatment period), approximately 12 weeks and 24 weeks (end of the maintenance period) after the start of therapy, and thereafter according to the clinical situation. (see section "Special instructions"). If transaminase activity is more than 3 times the upper limit of normal, the drug should be discontinued (see sections “Contraindications” and “Special Instructions”).
When increasing the dose, liver function should be monitored at the same frequency as at the beginning of the drug.
Duration of treatment
Drug therapy for depression should be continued for at least 6 months until symptoms of depression completely disappear.
Switching from SSRI/SNRI therapy to agomelatine therapy
Withdrawal syndrome is possible after stopping SSRIs/SNRIs.
To reduce the risk of withdrawal syndrome after stopping treatment with previously prescribed SSRIs/SNRIs, you must follow the instructions for medical use of these drugs.
Taking agomelatine can be started on the 1st day of gradually reducing the dose of SSRI/SNRI antidepressants (see section “Pharmacodynamics”).
Stopping treatment
If treatment is stopped, there is no need to gradually reduce the dose.
Elderly patients
The effectiveness and safety of agomelatine (at a dose of 25-50 mg/day) has been confirmed in elderly patients (younger than 75 years) with depression. There is no evidence of a significant effect in patients aged 75 years and older. In this regard, Valdoxan should not be prescribed to patients of this age group (see sections “Special instructions” and “Pharmacological action”). No dose adjustment is required depending on age (see section “Pharmacological action”).
Patients with kidney failure
In patients with severe renal failure, no significant changes in pharmacokinetic parameters were observed. 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 (see section "Special Instructions").
Patients with liver failure
Valdoxan is contraindicated in patients with liver failure (see sections “Contraindications”, “Special instructions” and “Pharmacokinetics”).
Reviews about Valdoxan. Application and instructions
After the unsuccessful treatment with Paxil, I stopped thinking about treatment with antidepressants for some time. Let me remind you that I thought (and still think so today) that the main reason for my condition was a “problem” with the blood circulation in the brain by 80-90%, and only a maximum of 20% “give” in favor of depression, which, in my opinion, is present, of course, I don’t argue, but it started precisely because of my constant poor health.
For those who came to this page directly from a search, let me remind you of my complaints:
Slight dizziness, fog in the head, periodic mild headaches Problems with sleep - waking up earlier, sleeping no more than 6-6.5 hours, feeling groggy in the morning Fatigue, decreased performance Increased irritability, sometimes touchiness, frequent lack of mood Moreover, it has been observed recently frequency of the condition: I feel pretty good for a couple of weeks, then it definitely gets worse for a week or two. But the improvements in well-being clearly do not reach the feeling of a healthy person, which I am already beginning to forget, to be honest.
I gained experience using Valdoxan, in general, unexpectedly. One acquaintance suggested that I talk with a psychotherapist he knew, which I hastened to take advantage of. I have no hope of at least slightly improving the situation with my early awakenings and lack of sleep, which clearly complicate my already sad existence.
My hope for a psychotherapist was not justified, I felt a clear lack of interest in my problem during the conversation, monosyllabic “cold” recommendations, and as a result, I was advised at least a month and a half course of the drug Valdoxan, an advertisement for which was on his desk (I immediately noted this, but not protested). Valdoxan was recommended as a new generation antidepressant, I believe in everything new and advanced, so I decided to try the drug on myself 
Valdoxan, an antidepressant. Active ingredient - agomelatine Agomelatine is active in validated models of depression (learned helplessness test, despair test, moderate chronic stress), as well as in models with desynchronization of circadian rhythms, as well as in experimental situations of anxiety and stress. It has been shown that agomelatine does not affect the uptake of monoamines and has no affinity for α-, β-adrenergic receptors, histamine receptors, cholinergic receptors, dopamine and benzodiazepine receptors.
Agomelatine enhances the release of dopamine and norepinephrine, especially in the prefrontal cortex and does not affect the concentration of extracellular serotonin. In experimental animal studies with simulated circadian rhythm desynchronization, agomelatine was shown to restore circadian rhythm synchronization through stimulation of melatonin receptors.
Agomelatine helps restore normal sleep structure, reduce body temperature and release melatonin.
The effectiveness of short-term use of agomelatine (therapy for 6-8 weeks) in doses of 25-50 mg in patients with major depressive episodes has been shown.
The use of agomelatine has also been shown to be effective in patients with more severe forms of depressive disorder (Hamilton scale score ≥ 25). Agomelatine was also effective for initially high levels of anxiety, as well as for combined anxiety and depressive disorders.
Dosage The recommended dose is 25 mg (1 tablet) 1 time/day in the evening. In the absence of clinical dynamics after two weeks of treatment, the dose can be increased to 50 mg (2 tablets) 1 time/day in the evening.
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.
Drug therapy for depression should be continued for at least 6 months for complete cessation of symptoms.
If treatment is stopped, there is no need to gradually reduce the dose.
Side effects In clinical studies, Valdoxan was administered to more than 3,900 patients with depression. Side effects were most often mild or moderate and were observed in the first 2 weeks of treatment. The most common symptoms were nausea and dizziness. The observed side effects were usually transient and generally did not require discontinuation of treatment. In some cases, it is difficult to distinguish between symptoms of depressive disorder and side effects of agomelatine therapy.
The frequency of side effects of agomelatine is given in the following gradation: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/100). 10,000, <1/1000); very rare (<1/10,000), unspecified frequency.
From the side of the central nervous system: often – headache, dizziness, drowsiness, insomnia, migraine; infrequently – paresthesia.
Mental disorders: often – anxiety; uncommon – agitation and associated symptoms*, such as irritability and restlessness, aggressiveness*, nightmares*, unusual dreams*; rarely – mania/hypomania* (these symptoms may also be a manifestation of the underlying disease), hallucinations*; unspecified frequency - suicidal thoughts or suicidal behavior.
From the digestive system: often – nausea, diarrhea, constipation, abdominal pain.
From the hepatobiliary system: often - increased activity of ALT and/or AST (more than 3 times compared to ULN when taking agomelatine in 1.3% of patients and in 0.7% when taking placebo); rarely - hepatitis, increased GGT* activity (more than 3 times compared to ULN), increased ALP activity* (more than 3 times compared to ULN).
From the skin and subcutaneous tissue: often – sweating; uncommon – eczema, skin itching*; rarely – erythematous rash.
From the side of the organ of vision: infrequently – blurred vision.
From the musculoskeletal system: often – back pain.
Other: often – fatigue.
What can I say, I took the drug for 8 weeks. There were no such mega side effects as Paxil. We can say that my condition has not changed at all. Yes, yes, exactly NO way. At first it seemed that it became somehow more fun, but then I realized that this was my usual “swing”. The problems with sleep did not go away, the dizziness did not stop, the feeling of confusion and fogginess did not go away. So... But that's not all!
Valdoxan, part two Quite recently (about three more years have passed) I turned to this drug again. My problems have not been resolved in any way, one might even say there is some deterioration, therefore, remembering Valdoxan and reading reviews on the Internet, I decided to try to take the course a second time. Only now, if necessary, try to increase the therapeutic dose and extend treatment for at least 3 months. I wasn’t afraid of side effects, because I didn’t have any, so I confidently took the package of the drug and started taking half a tablet for 3-4 days.
Imagine my surprise when, instead of the expected extension of the night’s sleep by at least 15-20 minutes, I woke up at exactly 3 a.m. (usually I wake up at 5 a.m.) and “at the drop of a hat.” And in the morning everything that follows is even greater weakness, severe dizziness and even a semblance of PA.
Coincidence was the first thing that came to mind. I took half a tablet for another 3 evenings - the same result: I wake up at 3.30 at most and can’t sleep anymore! I was amazed and upset! Most of the reviews about the drug were positive, and only once I came across a review with exactly the same manifestations while taking Valdoxan.
What to do, I had to stop the drug. My sleep returned to more or less normal, if my usual state can be called that, within a week. But I’m somehow afraid to try to start a course of Valdoxan again. These few days of night vigil with a cast iron head were very difficult for me.
But here I want to remind you that we are all different, the drug can act differently, it all depends on the body. And even in my case, the first course passed without side effects, but the second course “failed.” I think that says a lot.
I have no luck at all with antidepressants, apparently. The drug Remeron (Mirzaten) also failed the exam. More on this in the next post.
Comments (from archive):
Alexander 01/09/2014 And what drug did you choose? What do you advise?
Doc (Author) 01/10/2014 Oh, a slippery topic... I would focus on the fact that you need to do without drugs. I cope with almost all “feints” without the help of antidepressants. Where I endure in the hope that it will pass soon, where I don’t have to endure much, but one thing from time to time makes me try to take the course again - insomnia! Or rather, earlier awakening and inadequate sleep. This bullshit exhausts me to the extreme, and when it completely overwhelms me, I resign myself to the idea of trying yet another miracle of pharmacology again. At the moment I’m just in the “next testing”. This time the drug is Selectra. Since there is interest, in the coming days I will write a post on these “wheels”
Updated: Post about the drug Selectra
Boris Istomin 02/13/2014 I think you need to be treated in a hospital by a good psychiatrist. I tried a lot of things: Remeron and Cipralex and so on on this list. We treated and restored sleep with the help of Truxal according to the scheme 50-50-50 (1 week) 30-30-50 (2 week) 30-30-30 (3 week). It's not about pills, it's about quality therapy. Stop trying everything that comes across the shelves of pharmacies, go to the hospital, they will quickly restore everything.
Doc (Author) 02/14/2014 Believe me, I would have gone to the hospital if I knew that they would help. But in our area, I haven’t heard that there are smart doctors, but I don’t see the point in being treated by stupid ones.
Regarding pills - in general, I have a negative attitude towards any chemicals and will never take an extra pill without a reason, so “stop trying everything you come across” is a little misplaced. All the antidepressants that I mentioned were prescribed to me by doctors and I took them out of desperation, when my insomnia drove me to despair. But all my problems go away in periods, sometimes everything is fine for a couple of months, then bam and a couple of weeks can be erased from my life
Anatoly 05/28/2014 Started taking Valdoxan 25 mg once at night, today is day 10, for 8 days there were side effects that were quite unpleasant, sleep was disturbed, anxiety, PA. Days 9 and 10 were much better. We'll see and write about the results. Good luck to all.
Belka 06/21/2014 I felt like hell...my head was burning, I was dizzy, my limbs were numb, PA couldn’t swallow food. This was all against the backdrop of neurosis (I lost a loved one), a lot of medications and nothing. Valdoxan helped me after 2 weeks of taking it without side effects. I left the house for the first time in 3 months. I took it for 4 months in total. The drug is mild and not addictive. And my sleep returned to normal only after 3 weeks of taking it. Guys, for those who do not have an advanced condition, take a walk before bed for 1.5 hours and a glass of red wine will help you sleep strong.. this is not my recipe but a folk one)))) don’t get sick!!!
Anatoly 06/23/2014 And so, 5 weeks have passed since I started taking Valdoxan. This drug did not suit my anxiety disorder. In general, the condition only worsened. As a result, stopping the drug and returning to Cipralex. A few days on Cipralex and immediately much better. Everything after all, this is my personal AntD. It turns out that Valdoxan is good for depression, but it does not cure anxiety. Unfortunately (((
Anatoly 06/23/2014 By the way, I slept on it like a groundhog. Deep and pleasant. True, I didn’t have any special problems with sleep. When taking Valdoxan, after 1.5 hours I was already half awake)))
Natalya 08/14/2014 Valdoxan was prescribed by a cardiologist, no matter how strange it may sound. The cause was tachycardia caused by constant stress at work. Today is the fifth day of taking it, I take doses. 25 mg * 1 tab. for the night. I didn’t feel any side effects, everything was as usual. Only I became surprisingly calm, everyone around me noticed it. Moreover, the calmness is not general, but only as regards “nervous situations”, positive emotions remain). There is a reaction behind the wheel, but there is no “jerking” on the road; all the surrounding drivers suddenly became good). The sleep is amazing, even if I wake up at night, I immediately fall asleep again. Of course, it’s too early to give a final assessment of the drug, but so far at this stage it has pleased me and I don’t regret the money spent on it at all).
LYUBA 08/21/2014 WHAT DO YOU THINK CAN I GET RID OF P.A?????????????? TELL US FOREVER????????????????7
Doc (Author) 08/21/2014 You can! Stop being afraid of them and write in ALL CAPS in the comments. No joke about stopping being afraid of them
Lyuba 08/29/2014 Tell me how I can stop being afraid if I constantly think about it! Advise me that I’m already tired!!!
Doc (Author) 08/29/2014 At one time, during another PA, I lay down on the floor and thought “Whatever happens, it cannot be avoided” and prepared to die. After that, it became easier to tolerate the PA and in general they began to cover less and less often. I think you should see a psychotherapist. You can't waste your life thinking about bad things.
Lyuba 08/30/2014 how can you stop being afraid of them!!!! if they constantly bother you,,,tired of them.
love 08/30/2014 tell me when it starts to work!!!! I’ve been drinking it for 10 days already!!! compatible with atarax!!!!
Doc (Author) 08/30/2014 Who prescribed Valdoxan to you?
LYUBA 09/01/2014 PSYCHOTHERAPIST Now I’m taking atarax and voldaxan!!! and this weekend I’ll go to some kind of psychotherapy!!! but the condition is the same every day, sometimes it’s better... and then suddenly I’m afraid of everything at once!!! Is it all over for you already? and how did you identify yourself?
Doc (Author) 09/01/2014 I think it’s more logical to find out more details from your psychotherapist.
I can only say that ADs don’t start working right away, it’s different for everyone. And the therapeutic effect is achieved approximately a month after starting to take the medicine.
Second. Keep in mind that ADs (Valdoxan is no exception) affect everyone differently, to the point that you may not feel any improvement. It’s not without reason that they say that a competent doctor will “choose a drug for you.” This may not be so simple and the selection may, unfortunately, take quite a long period.
Vladimir 09/15/2014 I had PA. I took phenibut according to the 1-1-2 regimen for 1.5 months. Everything is over. Although, a little anxiety remained. But, most importantly, there are no attacks themselves!!!
Belka 09/18/2014 Hello everyone! Drink Valdoxan guys, it calms you down well, but don’t forget that we should also help our body. I recommend going for a massage to give the whole body a shake-up so that blood circulation and nerve endings start working. Think about healthy aging!! !
Alina 10/04/2014 I will sell Valdoxan for 900 rubles. I bought it for 1,700 rubles a month ago, but due to contraindications for breastfeeding, I didn’t drink it. Write to me by email every day.
Anatoly 10.28.2014 Gentlemen... Valdoxan does not work for anxiety. It copes well with depression, but not with anxiety and PA. I personally wasted 2 months. Which led to a change of doctor and drug. What is good about it is that that it is quite gentle at the beginning of use. Minimum side effects. Lyuba, you need to convey to your doctor that you are more worried about anxiety and PA. And you are being treated for depression. And covering with atarax will not help. In general, there is something better than atarax, it’s called stresam. Don’t take it for advertising. Don’t forget that choosing an antidepressant This is painstaking work, you can try a lot until you find yours. So be patient and life will sparkle with its former colors. Moreover, you have been sick for just a short time, and this means a favorable prognosis for recovery.
Anna 02.11.2014 My husband was prescribed Valdoxan by a cardiologist. After a hypertensive crisis, severe pain began. Every day at the same time, blood pressure began to rise, his arms and legs became icy, he was all wet from sweat, and was shaking. At first he took Valdoxan with clonazepam, then clonazepam was discontinued .now it’s much better. It’s stopped. I have a question. Anyone who took Valdoxan, were there any side effects related to potency?
Doc (Author) 11/03/2014 In most men, blood pressure causes some kind of sexual dysfunction. The question here is what exactly do you mean by “potency-related side effects”? As a rule, blood pressure helps to prolong sexual intercourse, in other words, it takes a man much more time to achieve orgasm than usual. For many, libido decreases against this background. In any case, if problems began around the same time as the start of taking blood pressure, then most likely the cause of these problems is the side effect of Valdoxan. As you take AD, these unpleasant phenomena smooth out, and after stopping AD, everything returns to normal.
Marina 12/13/2014 I’ve been on Valdoxan for almost a year, panic attacks, anxiety and fear, and the depression itself only went away in August, this is somewhere in the 10th month of taking it.. I don’t know whether to quit or not.. the attacks and all of the above were there for about 30 years, nothing conversations, conversations, trainings did not help. The effect was from Valdox. almost immediately, but stable remission for 5 months. There were no side effects, the main thing is not to stop taking it, even if something goes wrong at first, it happened to me, I suffered for two weeks, then everything went away. In general, I recommend it, I really didn’t want to get on the Andidep. but I simply didn’t have the strength anymore.
Marina 12/13/2014 .. acupuncture also helped me a lot, a year and a half was enough, the main thing is that the doctor was competent. VSD - there is no such diagnosis, look for the reason, everyone has it. I will not describe in detail everything that I have gone through in my entire life , all to no avail. So, a temporary lull. Change your thoughts, don’t accumulate grudges, do what you like, don’t live with people who cause harm. you feel pain, humiliation, insults, even if it’s your family!!! The root of our illness is constant dissatisfaction with our lives. But no one can change it except ourselves.
tat 12/22/2014 a week ago I was prescribed Valdoxan (before that I was prescribed Linuxin, but the side effects were driving me crazy, my head hurt, I was terribly nauseous, tremors, very weak, I couldn’t stand, and my heart was pounding so much that I thought I was going to die) so now I’m taking Valdoxan at night , and a little atarax to calm down, the psychotherapist prescribed me. I sleep well, my condition has noticeably improved, the feeling of anxiety and fear has disappeared, the only thing is that I often freak out and explode over trifles.
Alina 12/24/2014 I will sell Melitor (the name of the drug for Ukraine, the drug is the same agomelatine 25 mg, from the same company Servier as Valdoksan), there are 3 packs, I will send it by Russian post. terms until 2016. write for 1 pack – 600 rubles
julia 12/24/2014 Please tell me, I just don’t know what to do....it feels like I was born with VSD and only in 2009 after the birth of a child did I start to experience all the “charms” of this disease....very severe anxiety (no place I could find myself), fear of harming my baby, and everyone was so intrusive, but they were rare, and in the end it all “capped” with nasty insomnia. Everywhere I was, everyone shrugged, until I ended up in a paid clinic, in a hospital . Trust appeared immediately after they put me on a drip and I finally fell asleep (I felt like I was in heaven), they convinced me that I couldn’t cope without hell, select., for a long time (fevorin, rexitin, velaxin from cat.u my eyes were popping out of their sockets) and finally came to Cipralex 10 mg once in the morning and so on for 3.5 g - everything was fine, but as soon as I switched to half, the world lost its colors, and if you stop it completely, even gradually, we get withdrawal syndrome, besides the beginning of cognitive impairment, I got up in the morning for work and an hour later everything... fatigue, my brain couldn’t think straight, I began to talk, my blood pressure was low, and my pulse was under one hundred, like boiled water. As a result, in this clinic now they don’t know what to do, they say that it’s necessary change my life, I’m strong, I can handle it myself.....now after 2 months of suffering without Cipralex, I was prescribed Valdoxan, I’ve been taking it for 11 days, anxiety again, my heart is pounding, what should people do when this ends?? I visited highly praised psychotherapists, one had 8 sessions and to no avail, I don’t see the point, nonsense.... I’m tired and have no strength..... I have a wonderful daughter, a normal husband, lazy really, everything is more or less fine, but why is this all happening to me????? now my only hope is Valdoxan, I can’t relax my head, I have thoughts in my head, I can’t catch a positive thought and calm down
Elena 01/03/2015 I will sell 20 Valdoxan tablets inexpensively 89085555368 in Saratov
Ksenia 01/31/2015 I will sell Valdoxan in a large package for 1000 rubles. I bought it today as prescribed by a doctor; I didn’t know that this drug was an antidepressant. I won't accept it. Expiration date – until the end of 2021. Write by email -
Ksenia 01/31/2015 I will sell Valdoxan in a large package for 1000 rubles. I bought it today as prescribed by a doctor; I didn’t know that this drug was an antidepressant. I won't accept it. Expiration date – until the end of 2021. Write to the post office - St. Petersburg.
Andrey. 02/04/2015 Selling Valdoxan. Purchased on 2/2/15. Not useful. At a price of 1800 rubles. Urgently. Write by email
Natalya 03/09/2015 julia, VSD is not a death sentence, my daughter has had it for a long time, but we are coping with it, don’t take chemistry, buy Ivan tea, drink and if you have cheerful relatives, communicate with them, they will support and everything will pass, especially since you have a child and a good husband. if it’s really bad, try memoplant and stugeron, 3 months, almost everything went away, daughter is very happy
tata 03/09/2015 if someone doesn’t notice, then all antidepressants blow your mind, tested in practice
Varya 05/13/2015 Hello, I didn’t dare to write for a long time, I don’t know whether people read these reviews or not, but I’ll speak out anyway. Personally, I started taking Neurofulol on the advice of my mother-in-law when I experienced severe stress, I had to take it for a month, but after two days I stopped. At that time, it seemed that the world around me had collapsed and I had no strength for anything. Two months later I continued again, at the moment everything has improved, I am energized, my appetite has stabilized, I’ll tell you honestly that I feel comfortable with everything, I drink only 1 ton a day to maintain a good mood and VSD is not a death sentence, and it’s not scary for me I've been living and enjoying life since school
Vladimr 05/14/2015 are there any chemists on the forum? The chemical formula of Valdoxan is very similar to ecstasy, but of course there are some differences. Isn't the drug similar to it in its action?
Oleg 07/15/2015 I have diarrhea from Valdoxan, it just started today. If anyone has the same???
Svetlana 08/15/2015 I also have intestinal problems due to Valdoxan, I don’t know whether to drink it or tolerate it.
Svetlana 08/15/2015 That is, drink and tolerate it or quit)))
Andrey 08/17/2015 This is an antidepressant. If the doctor prescribed it, drink it. The article describes the experience of BREDOVO. Perhaps the first doctor did not know the nuances, and the second time the guy decided to do the bullshit himself. The drug is taken in one 25 mg tablet. If the effect is not noticeable within 1-2 weeks, it is taken 50 mg. If there is no change at 50 mg per day, then the drug is not for you.
Taking half a tablet, as the author wrote, is generally lame. With him waking up, this is psychosomatic, because... agomelatine is a derivative of melatonin, a sleep hormone.
Doc (Author) 08/17/2015 Andrey, are you a doctor? If so, what is your specialty, and more importantly, what is your experience? Second. This is not an article, this is a post on a personal blog. Big difference in my opinion.
Without seeing the patient and the results of the examination, it is at least unprofessional to say “this is psychosomatic when he wakes up,” because this can be a manifestation of many diseases, especially if there are organic changes in the GM. And regarding the minimum dosages, you’d better argue with psychotherapists who prescribe medications and have real experience and real results
Attention!
We recommend that you read our new article Natural antidepressants - getting rid of depression, panic attacks and insomnia without side effects
Side effects
In clinical studies, Valdoxan was administered to more than 7,900 patients with depression. Side effects were most often mild or moderate and were observed in the first 2 weeks of treatment. The most common symptoms were nausea and dizziness. The observed side effects were usually transient and generally did not require discontinuation of treatment.
The frequency of side effects of agomelatine is given in the following gradation: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/100). 10,000, <1/1000); very rare (<1/10,000), unspecified frequency.
From the side of the central nervous system: often - headache, dizziness, drowsiness, insomnia, migraine; infrequently - paresthesia, restless legs syndrome*.
Mental disorders: often - anxiety; uncommon - agitation and associated symptoms*, such as irritability and restlessness, aggressiveness*, nightmares*, unusual dreams*; rarely - mania/hypomania* (these symptoms may also be a manifestation of the underlying disease (see section “Special Instructions”)), hallucinations*; unspecified frequency - suicidal thoughts or suicidal behavior (see section "Special instructions").
From the gastrointestinal tract: often - nausea, diarrhea, constipation, abdominal pain, vomiting*.
From the hepatobiliary system: often - increased activity of ALT and/or AST (more than 3 times compared to ULN in 1.4% of patients while taking agomelatine at a dose of 25 mg per day and in 2.5% of patients when taking agomelatine at a dose of 50 mg per day, compared to 0.6% with placebo in clinical studies); rarely - hepatitis, increased gamma-GGT* activity (more than 3 times compared to ULN), increased ALP activity* (more than 3 times compared to ULN), liver failure*(1), jaundice*.
From the skin and subcutaneous tissue: often - sweating; uncommon - eczema, skin itching*, urticaria*; rarely - erythematous rash, facial swelling and angioedema*.
On the part of the hearing organ: infrequently - tinnitus.
From the side of the organ of vision: infrequently - blurred vision.
From the musculoskeletal system: often - back pain.
General disorders: often - fatigue.
Data from additional examinations: rarely - weight gain, weight loss.
* — the frequency of adverse reactions identified by spontaneous reports was assessed based on data from clinical studies.
(1) Only a few cases of death or liver transplantation have been reported in patients with preexisting risk factors for liver disease.
results
18 of 20 patients completed the complete course of therapy with Valdoxan; 2 patients were prematurely excluded from the therapeutic program: in one case, on the 14th day of therapy due to a deterioration in the patient’s mental state (increased symptoms of depression with the addition of hypochondriacal delusions), in another case, also on the 14th day of therapy due to the development of undesirable phenomena.
The majority of patients (14 people - 78%) from the 3rd week of therapy received Valdoxan at a dose of 50 mg per day, and 4 (22%) patients continued treatment at an initial dose of 25 mg per day.
A significant reduction in total indicators of anxiety and depression on the HADS scale was observed after just 1 week of therapy (see Table 2). By this time, the average total score on the scale decreased from 26.05 to 22.52 ( p
<0.01), the average improvement rate was 13.14%.
By the 14th day of therapy, the average total score continued to decrease and amounted to 16.88 ( p
= 0.0006), the average degree of improvement was 34.46%. On the 28th day of therapy, this indicator was 14.58 points, the average degree of improvement was 43.46%. By the end of the therapeutic course (on the 42nd day of therapy), the average total score on the HADS scale decreased to 10.0, and the average degree of improvement in the group reached 61.61% (see Table 2, Fig. 1).
Rice.
1. Dynamics of group average total indicators (in points) on the HADS scale during therapy with Valdoxan in elderly patients with depression. Here and in Fig. 2: differences compared to baseline: * - p<0.01 (paired Wilcoxon test). The level of anxiety disorders, assessed on the HADS scale, at the beginning of therapy was 13.0 points and significantly decreased throughout the therapeutic course of Valdoxan: after 1 week the anxiety level was 10.17 points, by the 14th day of therapy - 7.41, by the 28th - 6.70, and by the end of therapy it had decreased to 4.41 points (see Table 2, Fig. 1).
The level of depression on the HADS scale before treatment was 13.58 points, it progressively decreased with each subsequent visit: by the 7th day of therapy - to 12.23 points, by the 14th - to 9.41, by the 28th - up to 7.88 and by the 42nd day - up to 5.58. In the group as a whole, the depressive component was reduced by 58.91% compared to the initial level. As one would expect, the dynamics of reduction in the anxiety component of depression were somewhat faster than the reduction in depressive disorders themselves. These differences leveled out by the end of the 1st month of therapy (see Table 2, Fig. 1).
Anhedonia is considered one of the leading manifestations of depression and is often considered as its potential constitutional marker. Anhedonia is understood as dissatisfaction with the incompleteness of mental functions, the impossibility of self-expression, the bitterness of existence, depriving the patient of the opportunity to receive pleasure and positive emotions. Therefore, the effective therapeutic effect of an antidepressant on the manifestations of anhedonia can be considered as an important component of the success of depression treatment. During therapy with Valdoxan, positive dynamics in the form of a reduction in anhedonia were noted already in the early stages of treatment, with a subsequent increase in the positive effect. According to the SHAPS anhedonia rating scale, a statistically significant reduction in the manifestations of anhedonia was noted after 2 weeks of treatment. By this time, anhedonia was reduced by 31.57% and subsequently continued to decrease: by the 28th day - by 52.11% and by the end of therapy - by 69.29% (see Table 2, Fig. 2).
Rice. 2. Dynamics of the group average total index of anhedonia (in points) on the SHAPS scale during therapy with Valdoxan in elderly patients with depression.
After completion of therapy with Valdoxan, the quality of life of patients also improved. Analysis of the dynamics of quality of life indicators, carried out using the SF-36 questionnaire, showed an improvement in all assessed parameters compared to the baseline. Indicators of both physical and psychological components of health improved significantly (Table 3). The greatest improvements concerned indicators such as life and social activity and mental health (Fig. 3).
Table 3. Dynamics of group average indicators of quality of life according to the SF-36 questionnaire in patients treated with Valdoxan
Rice. 3. The effectiveness of therapy in terms of quality of life according to the SF-36 questionnaire in patients treated with Valdoxan.
One of the features of depression in old age is the frequent presence of cognitive disorders of varying severity. Therefore, choosing a drug that does not have a negative effect on cognitive functioning is one of the most important tasks of geriatric psychopharmacotherapy. A study of the effect of Valdoxan on the cognitive functioning of patients, carried out using the MMSE test, showed not only the absence of deterioration, but also some improvement in this indicator after the end of course therapy. The average initial group average score on the MMSE scale increased by the end of treatment from 26.76±3.30 to 28.17±2.0 points, i.e., improved by 5.27% (see Table 2). This effect of the drug is probably associated with a reduction in the anxiety component and impaired concentration associated with depression.
When assessing the effectiveness of Valdoxan therapy on the CGI scale, rapid positive dynamics were noted. Already by the 14th day of therapy, improvement of varying degrees of severity was noted in 55% of patients, in 35% the condition remained without significant dynamics, and in 2 (10%) patients the condition worsened (Table 4). On the 28th day of therapy, an improvement in mental state on the CGI scale was observed in 88.9% of patients, and by the end of therapy - in 94.5% (Fig. 4). In general, the results of the analysis of tolerability of therapy with Valdoxan showed good tolerability of therapy. Adverse events that occurred in 2 patients were mild or moderate. In 1 patient, on the 14th day of therapy, there was a deterioration in the condition, which was manifested by worsening symptoms of depression with the addition of hypochondriacal delusions, and therefore the patient was excluded from this therapeutic program. In the second case, the deterioration of the condition was associated with the development of an adverse event in the form of an allergic reaction, which also led to early discontinuation of the drug.
Table 4. Distribution of patients with varying degrees of change in condition according to the CGI scale during therapy with Valdoxan in relation to the total number of patients
Rice. 4. The proportion of patients with varying degrees of change in CGI scale indicators (in % of the total number of patients) during therapy with Valdoxan.
Overdose
Data on agomelatine overdose are limited.
Symptoms: drowsiness, epigastric pain, restlessness, weakness, anxiety, agitation, tension, dizziness, cyanosis, malaise. When the patient took agomelatine at a dose of 2450 mg, the condition returned to normal independently, without disturbances in the cardiovascular system or changes in laboratory parameters.
Treatment: Specific antidotes for agomelatine are not known. Symptomatic treatment and monitoring are carried out in specialized departments with subsequent observation.
Drug interactions
Potential influence of other medicinal products
Agomelatine is metabolized 90% in the liver with the participation of cytochrome P450 1A2 (CYP1A2) and 10% by CYP2C9/19. Therefore, any drugs whose metabolism depends on these isoenzymes may increase or decrease the bioavailability of agomelatine.
Fluvoxamine is a strong inhibitor of the CYP1A2 isoenzyme and a moderate inhibitor of the CYP2C9 isoenzyme and significantly slows down the metabolism of agomelatine, while the concentration of agomelatine increases approximately 60 (12-412) times. Therefore, the simultaneous use of agomelatine and strong inhibitors of the CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) is contraindicated.
The simultaneous administration of agomelatine and estrogens, which are moderate inhibitors of the CYP1A2 isoenzyme, leads to an increase in the concentration of agomelatine several times. Although the combined use of agomelatine and estrogens was not accompanied by a deterioration in the safety profile of the therapy, caution should be exercised when co-prescribing agomelatine with other moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin) until sufficient clinical experience has been gained (see section "Special Instructions").
Rifampicin, as an inducer of both cytochromes involved in the metabolism of agomelatine, can reduce the bioavailability of agomelatine. It has been shown that smoking, by inducing the CYP1A2 isoenzyme, reduces the bioavailability of agomelatine, especially in patients who smoke excessively (≥15 cigarettes/day) (see section “Pharmacokinetics”).
Potential effects of agomelatine on other medicinal products
In vivo, agomelatine does not induce cytochrome P450 isoenzymes. Agomelatine does not inhibit the CYP1A2 isoenzyme in vivo or other cytochrome P450 isoenzymes in vitro. Therefore, agomelatine does not affect the concentration of drugs whose metabolism is associated with these isoenzymes.
Drugs that are significantly bound to plasma proteins
Agomelatine does not change the free concentration of drugs that are significantly bound to plasma proteins and, in turn, they do not affect the concentration of agomelatine.
Other medicines
There was no pharmacokinetic and pharmacodynamic interaction between agomelatine and drugs commonly used in the target patient population: benzodiazepines, lithium, paroxetine, fluconazole and theophylline.
Alcohol
The use of agomelatine in combination with alcohol is not recommended.
Electroconvulsive therapy (ECT)
There are no data on the use of agomelatine concomitantly with electroconvulsive therapy (ECT). Since agomelatine did not cause seizures in animal studies, adverse effects from the combined use of agomelatine and ECT seem unlikely.
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 (see section "Side effects"). 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 liver dysfunction, such as obesity/overweight/non-alcoholic fatty liver disease, diabetes, alcohol abuse and taking drugs that can cause liver dysfunction liver.
Before starting therapy, liver function tests should be performed in all patients, and therapy cannot be started if the level of liver enzymes ALT and/or AST is more than 3 times the ULN (see section "Contraindications").
Caution should be exercised when prescribing Valdoxan to patients with initially elevated transaminase activity (above ULN, but not more than 3 times relative to ULN).
Frequency of liver function tests:
- before starting therapy;
and further:
- 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, the test should be repeated 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);
- increase in transaminase levels by more than 3 times compared to ULN.
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 (75 years and older) has not been established. In this regard, Valdoxan should not be prescribed to patients in this age group (see sections “Dosage regimen” and “Pharmacological action”).
Elderly patients with dementia
Valdoscan 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 disorder, 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 CYP1A2 isoenzyme inhibitors
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 agomelatine concentrations (see sections “Contraindications” and “Drug Interactions”).
Patients with lactose intolerance
The drug should not be used in patients with lactose intolerance: lactase deficiency, galactosemia and glucose-galactose malabsorption (see section “Contraindications”).
Impact on the ability to drive vehicles and operate machinery
No studies have been conducted to study the effect of the drug 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.
Material and methods
The study included patients aged 60 years and older with depression of varying severity who were treated in the geriatric psychiatric clinic of the Scientific Center for Mental Health.
The patients were prescribed Valdoxan in standard doses of 25-50 mg per day for 42 days. Valdoxan (Valdoxan) was prescribed in accordance with the instructions 1 time per day at the same time (evening) at a dose of 25 mg (1 tablet) in the first 2 weeks of therapy. If necessary, the daily dose was increased to a maximum of 50 mg 1 time (in the evening).
The study included 20 patients, 6 (30%) men and 14 (70%) women aged 60 to 79 years (average - 69.9±6.06 years) (Table 1).
Table 1. Demographic and clinical characteristics of the group of patients treated with Valdoxan
All patients were diagnosed with a major depressive episode (DE) in accordance with the DSM-IV-TR or ICD-10 classification, including 2 patients with a single episode of DE, 13 with a depressive phase within the framework of recurrent depressive disorder (RDD), and 5 - within the framework of bipolar affective disorder (BD). The patients had no history of other mental disorders or primary organic diseases.
According to ICD-10 criteria, depression corresponded to mild DE in 6 (30%) patients, moderate DE in 13 (65%) patients, and severe DE in 1 (5%) (see Table 1).
All patients underwent a full clinical examination (psychopathological, psychometric, therapeutic and neurological).
To assess the therapeutic effectiveness of treatment, standardized rating scales were used: the Hospital Anxiety and Depression Scale (HADS), the Snight-Hamilton Anhedonia Rating Scale (SHAPS), and the Clinical Global Impression (CGI) scale. The patients' condition was assessed on these scales before the start of treatment (day 0), on the 7th, 14th, 28th and 42nd days of therapy. To assess the quality of life of patients, a special questionnaire SF-36 was used. The Mini Mental State Examination (MMSE) was used to assess cognitive functioning. These questionnaires were assessed before and after the end of treatment (on the 42nd day of therapy).
The effectiveness of therapy was determined by the degree of reduction in the average scores for the group of patients on the SHAPS, HADS, CGI-S and CGI-I scales on the 7th, 14th, 28th and 42nd days of treatment in relation to the initial assessment (in %).
Adverse effects of therapy were assessed using the UKU drug side effect scale before the start, on the 7th and 42nd days of treatment.
The HADS consists of 14 items and has 2 subscales (to assess levels of anxiety and depression). When assessing the severity of anxiety and depression, the total score for each subscale was taken into account. The total score from 0 to 7 corresponds to the norm, 8-10 points - subclinical level, 11 points and above - clinically expressed anxiety and depression.
The CGI scale used a graded assessment of the severity of the condition (CGI-S subscale), where 1 point corresponded to the fact that the patient is not sick, 2 points - borderline state (subclinical level), 3 points - mild, 4 points - moderate, 5 points - moderate-severe condition, 6 points - severe condition, 7 points - extremely severe condition. The CGI-I subscale assessed the dynamics of the state during therapy compared to its initial level: 1 point corresponded to pronounced, 2 points to moderate and 3 points to minimal improvement; 4 points corresponded to no change, 5 points to minimal deterioration, 6 points to deterioration, and 7 points to marked deterioration.
The SF-36 questionnaire is used to assess the quality of life of patients. It consists of 36 items, which are grouped into 8 scales: physical functioning, role functioning, bodily pain, general health, vitality, social functioning, emotional state and mental health. The results are scored on each of 8 scales, which are designed in such a way that a higher score indicates a better level of quality of life. The following indicators are quantified: 1. Physical functioning (PF), reflecting the degree to which physical condition limits the performance of physical activities (self-care, walking, climbing stairs, carrying heavy objects, etc.). Low scores on this scale indicate that the patient's physical activity is significantly limited by his health status. 2. Role functioning due to physical condition (RP) - the influence of physical condition on daily role activities (work, daily duties). Low scores on this scale indicate that daily activities are significantly limited by the patient's physical condition. 3. Pain intensity (BP) and its impact on the ability to perform daily activities. Low scores on this scale indicate that pain significantly limits the patient's activity. 4. General health (GH) - the patient’s assessment of his or her health status. 5. Vital activity (VT) implies feeling full of strength and energy or, on the contrary, exhausted. Low scores indicate patient fatigue and decreased vital activity. 6. Social functioning (SF), determined by the degree to which physical or emotional conditions limit the social activities of patients. Low scores indicate a significant limitation of social contacts, a decrease in the level of communication due to deterioration of physical and emotional condition. 7. Role functioning due to emotional state (RE) involves assessing the extent to which the emotional state interferes with the performance of work or other daily activities (including more time spent, less work, less quality work, etc.). Low scores on this scale are interpreted as a limitation in the performance of daily work due to a deterioration in the emotional state. 8. Mental health (MH) characterizes mood, the presence of depression, anxiety, and a general indicator of positive emotions. Low scores indicate the presence of depression, anxiety, and mental ill-being. All scales are grouped into two indicators: “physical health component” (Physical health - PH) and “psychological health component” (Mental Health - MH).
The level of cognitive activity was assessed using the MMSE scale, according to which a total score of 28 points and above corresponds to the norm; a score from 25 to 27 points indicates mild cognitive impairment; 24 points and below indicate cognitive deficit in the degree of dementia.
At the beginning of therapy, the anxiety component of depression according to HADS was on average 13.0±4.13 points for the group, the depressive component was 13.58±3.44 points, the average total score of anxiety and depression was 26.05±6.29 points, and the average anhedonia level score (on the SHAPS scale) was 8.8±3.12 points. The level of cognitive activity of most patients corresponded to the age norm with an average group score on the MMSE scale of 26.76±2.30 points (Table 2).
Table 2. Dynamics of average group indicators (in points) on rating scales during therapy with Valdoxan
In the study group, a high burden of patients with concomitant chronic somatic pathology was established. The total number of chronic somatic diseases averaged 3.85±1.42 per patient. The most common diagnoses in the studied cohort of patients were cerebrovascular (90%) and cardiovascular (50%) pathology, as well as diabetes mellitus (25%).
Statistical analysis of the results was carried out using the Statistica 6.0 for Windows program using nonparametric methods (paired Wilcoxon test). To describe quantitative characteristics, average values and standard deviations were used. Differences were considered significant at p
<0,05.
Pregnancy and lactation
There are no or limited data on the use of agomelatine during pregnancy (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.
It is not known whether agomelatine passes into breast milk in women during lactation. Experimental studies in animals have shown that agomelatine and its metabolites pass into breast milk. If treatment with agomelatine is necessary, breastfeeding should be discontinued.
