Instructions for use VELAXIN® tablets

Pharmacological properties of the drug Velaxin

Venlafaxine ((±)-1-[dimethylamino-1-(methoxy-phenyl)-ethyl] cyclohexanol hydrochloride) is an antidepressant with a new chemical structure that cannot be classified as tricyclic, tetracyclic or other known antidepressants. It is a racemic mixture of two active enantiomers. The mechanism of the antidepressant effect of venlafaxine is associated with increased neurotransmitter activity of the central nervous system. Venlafaxine and its main metabolite O-desmethyl venlafaxine (ODV) are potent inhibitors of neuronal reuptake of serotonin and norepinephrine, and also inhibit dopamine reuptake. In addition, both single and chronic administration of venlafaxine and EDV attenuates β-adrenergic reactions. They are equally effective in influencing the reuptake of neurotransmitters. Venlafaxine does not inhibit MAO activity. Venlafaxine has no affinity for opiate, benzodiazepine, phencyclidine, or N-methyl-d-aspartate (NMDA) receptors; it also does not affect the release of norepinephrine from brain tissue. With repeated use of the drug, equilibrium concentrations of venlafaxine and its only active metabolite in the blood plasma are achieved within 3 days. Venlafaxine and EDV have linear pharmacokinetics with total daily doses ranging from 75 to 450 mg. Absorption of venlafaxine after taking a single dose of the drug orally is almost 92%, absolute bioavailability is about 45%. After administration of Velaxin extended-release capsules, maximum plasma concentrations of venlafaxine and its active metabolite EDV are achieved within approximately 6 and 8 hours, respectively. The rate of absorption of venlafaxine released from extended-release capsules is less than the rate of its elimination. Therefore, the average half-life of venlafaxine from the body after taking Velaxin (15±6 hours) is actually the half-life in the absorption phase, and not the half-life in the distribution phase (5±2 hours), which is observed after the use of tablets. After administration of venlafaxine in equivalent doses in tablet or extended-release capsule form, venlafaxine AUC exposure and EDV were similar in both dosage forms, and their plasma concentrations were slightly lower after administration of venlafaxine in capsule form. Thus, extended-release capsules provide slower absorption but the same extent of absorption (i.e., AUC) as Velaxin tablets. Venlafaxine is extensively metabolized during the initial passage through the liver, mainly with the participation of CYP 2D6, with the formation of the main metabolite EDV. It is also metabolized to N-desmethyl venlafaxine and some other metabolites with the participation of CYP 3A3/4. Venlafaxine and its metabolites are excreted mainly by the kidneys. Approximately 78% of the administered dose of venlafaxine is determined in the urine over 48 hours in the form of unchanged venlafaxine, unconjugated EDV, conjugated EDV or other metabolites. In case of renal and hepatic insufficiency, the half-life of venlafaxine and its active metabolite EDV increases. Taking the drug with food does not affect the absorption of venlafaxine and the further formation of EDV. The age and gender of the patient do not affect the pharmacokinetics of the drug. The drug does not accumulate in the body. Velaxin extended-release capsules contain microspheres that, when entering the gastrointestinal tract, slowly release the active component. The insoluble part of these microspheres is excreted in the feces.

Velaxin, 37.5 mg, tablets, 28 pcs.

Discontinuation of the drug Velaxin®.

As with other antidepressants, abrupt cessation of venlafaxine therapy, especially after high doses, may cause withdrawal symptoms, and it is therefore recommended that the dose be gradually reduced before discontinuing the drug. The length of the period required to reduce the dose depends on the dose size, duration of therapy, as well as the individual sensitivity of the patient.

When prescribing Velaxin® tablets to patients with lactose intolerance, the lactose content should be taken into account (56.62 mg - in each tablet 25 mg; 84.93 mg - in each tablet 37.5 mg; 113.24 mg - in each tablet 50 mg ; 169.86 mg - each tablet contains 75 mg).

In patients with depressive disorders, the possibility of suicide attempts should be considered before starting any drug therapy. Therefore, to reduce the risk of overdose, the initial dose of the drug should be as low as possible, and the patient should be under close medical supervision.

In patients with affective disorders when treated with antidepressants, incl. venlafaxine, hypomanic or manic states may occur. Like other antidepressants, venlafaxine should be used with caution in patients with a history of mania. Such patients require medical supervision.

Like other antidepressants, venlafaxine should be administered with caution to patients with a history of epileptic seizures. Treatment with venlafaxine should be interrupted if epileptic seizures occur.

Patients should be warned to seek immediate medical attention if rash, urticaria, or other allergic reactions occur.

In some patients, while taking venlafaxine, a dose-dependent increase in blood pressure was noted, and therefore regular monitoring of blood pressure is recommended, especially during the period of clarification or increase in dosage.

An increase in heart rate may occur, especially during high doses. Caution is recommended for tachyarrhythmia.

Patients, especially the elderly, should be warned about the possibility of dizziness and impaired balance.

Like other serotonin reuptake inhibitors, venlafaxine may increase the risk of bleeding into the skin and mucous membranes. Caution is necessary when treating patients predisposed to such conditions.

While taking venlafaxine, especially in conditions of dehydration or decreased blood volume (including in elderly patients and patients taking diuretics), hyponatremia and/or syndrome of insufficient ADH secretion may occur.

Mydriasis may occur while taking the drug, and therefore it is recommended to monitor IOP in patients prone to increasing it or suffering from angle-closure glaucoma.

Venlafaxine has not been studied in patients with recent myocardial infarction and decompensated heart failure. The drug should be prescribed to such patients with caution.

Clinical trials conducted to date have not revealed tolerance or dependence to venlafaxine. Despite this, as with other drugs that act on the central nervous system, the physician should closely monitor patients to identify signs of drug abuse. Careful monitoring and observation is necessary for patients with a history of such symptoms.

Women of childbearing potential should use appropriate contraception while taking venlafaxine.

Although venlafaxine does not affect psychomotor and cognitive functions, it should be taken into account that any drug therapy with psychoactive drugs may reduce the ability to make judgments, think or perform motor functions. The patient should be warned about this before starting treatment. If such effects occur, the degree and duration of restrictions should be determined by a physician. Drinking alcohol is also not recommended.

Use of the drug Velaxin

Capsules should be taken whole with a meal with liquid. Capsules should not be divided, crushed, chewed or dissolved. The daily dose should be taken in one dose (morning or evening) at the same time. Depression The recommended dose is 75 mg/day in one dose. If, taking into account the course of the disease, a higher dose is necessary, for example, in case of severe depression or inpatient treatment of the patient, the recommended initial dose may be 150 mg/day in one dose. After this, the daily dose can be increased by 37.5–75 mg at intervals of ≥2 weeks, but not less than 4 days until the required therapeutic effect is achieved. The recommended maximum dose of Velaxin is 225 mg/day for moderate depression and 350 mg for severe depression. After achieving the desired therapeutic effect, the dose should be gradually reduced to the minimum effective, taking into account the individual response and tolerability of each patient. When used in high doses, the risk of developing side effects of the drug increases. Generalized anxiety disorders and social anxiety disorders (social phobia) The recommended dose of Velaxin is 75 mg/day in one dose. If after 2 weeks of treatment there is no noticeable improvement in the condition, the daily dose can be increased to 150 mg/day in one dose. When used in a daily dose of 75 mg, an anxiolytic effect is observed after 1 week. Prevention of relapses or new episodes The effectiveness of venlafaxine has been established with long-term therapy (up to 12 months for depression and social phobia; up to 6 months for generalized anxiety disorders). Treatment of acute episodes of depression must be continued for at least 6 months. The doses typically used to prevent a relapse or new episode are similar to those used to treat patients with a primary episode. It is necessary to regularly (at least once every 3 months) examine the patient to monitor the effectiveness of long-term therapy with Velaxin. Transfer of patients receiving therapy with Velaxin in the form of tablets to taking a capsule form of the drug Patients with depression receiving Velaxin tablets in a therapeutic dose can be transferred to taking the drug in the form of long-acting capsules with the appointment of the nearest equivalent dose. Sometimes individual dose adjustment may be required. Renal failure When the glomerular filtration rate is 30 ml/min, no dose adjustment is required. With a glomerular filtration rate of 10–30 ml/min, the dose should be reduced by 50%. Due to the increased half-life of venlafaxine and its active metabolite in these patients, the daily dose should be taken in one dose. It is not recommended to use venlafaxine if the glomerular filtration rate is ≤10 ml/min, since there is insufficient data on therapy in these patients. For patients on hemodialysis, the daily dose of the drug should be reduced by 50% and, if possible, used after completion of the hemodialysis procedure. Liver failure In mild liver failure (prothrombin time ≤14 s), no dose adjustment is required. In case of moderately severe liver failure (prothrombin time - 14–18 s), the dose should be reduced by 50%. It is not recommended to use venlafaxine in severe hepatic impairment (prothrombin time 18 s), as there is insufficient data on this therapy. Elderly patients Caution should be exercised when prescribing the drug to elderly patients (due to the possibility of renal dysfunction), and the drug is prescribed in the minimum effective dose. When increasing the dose, the patient should be under regular medical supervision. Cancellation of Velaxin Abrupt cessation of Velaxin therapy, especially after taking the drug in high doses, can cause the development of withdrawal syndrome, and therefore a gradual dose reduction is recommended before complete discontinuation of the drug. If the drug has been used in high doses for 6 weeks, a dose reduction period of at least 2 weeks is recommended. The length of the period required to reduce the dose depends on the dose size, duration of therapy, as well as the individual sensitivity of the patient.

Velaxin extended-release capsules 75 mg 28 pcs.

Velaxin capsules should be taken orally with meals. Each capsule must be swallowed whole with sufficient liquid. Capsules should not be broken, crushed, chewed or placed in water. The entire daily dose, consisting of one or more capsules, should be taken in one dose (morning or evening) at approximately the same time each time. For depression, the recommended starting dose is 75 mg once a day every day. In many cases, this dose has a sufficient therapeutic effect. If the doctor considers it appropriate to use a higher dose (for example, for severe depression or conditions requiring hospital treatment), a dose of 150 mg 1 time per day can be immediately prescribed. Subsequently, the daily dose can be increased stepwise by 75 mg at intervals from 4 days to two weeks until the desired effect is achieved. The maximum recommended daily dose is 225 mg, for severe depression - 375 mg. After achieving the desired therapeutic effect, the doctor can gradually reduce the dose to a sufficiently effective level. For generalized anxiety disorders and social phobias, the recommended starting dose is 75 mg once a day daily. In most cases, this dose is sufficient; a positive effect is usually observed after 1 week. If after two weeks of treatment there is no significant improvement, the doctor may increase the daily dose to 150 mg at a time. Maintenance therapy and relapse prevention. Treatment for depressive episodes should be continued continuously for several months. Velaxin is effective with long-term therapy (lasting 6–12 months). For maintenance therapy and to prevent relapse or new episodes, doses effective in treating the initial episode are used. Visit your doctor regularly, at least once every 3 months, to monitor the effectiveness of Velaxin therapy. Special groups of patients. Doses for the treatment of elderly patients and patients with impaired liver or kidney function are usually lower than usual and should be selected individually by the doctor, taking into account the functional state of the kidneys and liver. For patients on hemodialysis, the daily dose of venlafaxine should be halved, and they should take the drug, if possible, after the end of the hemodialysis session. Transferring patients from Velaxin tablets. Your doctor may prescribe you Velaxin extended-release capsules instead of Velaxin tablets. In this case, he will determine which dose of Velaxin extended-release capsules is closest to the total daily dose of Velaxin tablets you are taking. Discontinuation of the drug. After abruptly stopping taking the drug Velaxin, the following symptoms may be observed: fatigue, drowsiness, headache, nausea, vomiting, dry mouth, dizziness, diarrhea, insomnia, restlessness, anxiety, nervous irritability, confusion, pathologically elevated mood, numbness, sweating. These side effects are not dangerous and usually go away spontaneously. However, as with other antidepressants, it is important to gradually reduce the dose before stopping the drug, especially after taking high doses. If high doses have been used for more than 6 weeks, dose reduction should take at least 2 weeks. The duration of the course of treatment is determined by the doctor. Discontinuation of the drug or dose change should be carried out as prescribed and under the supervision of a physician.

Contraindications to the use of the drug Velaxin

Hypersensitivity to any component of the drug. Simultaneous use of any antidepressant from the MAO inhibitor group, as well as for 14 days after discontinuation of irreversible MAO inhibitors. After complete discontinuation of venlafaxine, therapy with MAO inhibitors can be started no earlier than 7 days later. Diseases of the cardiovascular system (heart failure, coronary artery disease, ECG changes - pre-existing increase in the QT on the ECG), hypertension (arterial hypertension), electrolyte imbalance. Age up to 18 years. During pregnancy and breastfeeding.

Side effects of the drug Velaxin

Side effects are divided by body system and frequency of occurrence: very often (1/10); often (≤1/10, but 1/100); sometimes (≤1/100, but 1/1000); rare (≤1/1000); very rare (≤1/10,000). General symptoms: very often - asthenia, headache; often - abdominal pain, chills, increased body temperature; rarely - anaphylaxis. Gastrointestinal tract: very often - constipation, nausea; often - loss of appetite, diarrhea, vomiting; sometimes - bruxism, reversible increase in the activity of liver enzymes; rarely - gastrointestinal bleeding; very rarely - pancreatitis. Cardiovascular system: often - tachycardia, hypertension (arterial hypertension), dilatation of blood vessels; sometimes - hypotension/orthostatic hypotension, loss of consciousness, arrhythmias, tachycardia; very rarely - pirouette-type tachycardia, increased QT on ECG, ventricular tachycardia, ventricular fibrillation. Respiratory system: often - difficulty breathing, yawning; very rarely - eosinophilic infiltrates in the lungs. Nervous system: very often - dizziness, dry mouth, insomnia, anxiety, drowsiness; often - unusual dreams, agitation, anxiety, confusion, increased muscle tone, paresthesia, tremor; sometimes - apathy, hallucinations, myoclonus; rarely - ataxia with impaired balance and coordination of movements, speech impairment, including dysarthria, mania or hypomania, as well as manifestations that resemble neuroleptic malignant syndrome (NMS), seizures, serotonergic syndrome; very rarely - delirium, extrapyramidal disorders, including dyskinesia and dystonia, psychomotor agitation/akathisia. Genitourinary system: very often - anorgasmia, erectile dysfunction, impaired ejaculation and orgasm; often - frequent urination, decreased libido, menstrual irregularities; sometimes - urinary retention, menorrhagia; rarely - galactorrhea. Sense organs: often - blurred vision and accommodation, mydriasis, noise and ringing in the ears; sometimes - a change in taste sensations. Skin: very often - sweating; often - skin rashes and itching; sometimes - angioedema, maculopapular rash, urticaria, photosensitivity, alopecia; rarely - erythema multiforme, Stevens-Johnson syndrome. Blood system: sometimes - ecchymosis, bleeding from the mucous membrane; rarely - increased bleeding time, hemorrhage, thrombocytopenia; very rarely - agranulocytosis, aplastic anemia, neutropenia, pancytopenia. Metabolism: often - increased cholesterol levels in the blood serum, increase or decrease in body weight; sometimes - hyponatremia, increased activity of liver transaminases; rarely - hepatitis; very rarely - increased prolactin levels. Musculoskeletal system: often - arthralgia, myalgia; sometimes - muscle spasms; very rarely - rhabdomyolysis.

Velaxin (Venlafaxine)

In most patients, an overdose of Velaxin manifests itself only in mild symptoms. However, severe toxicity has been reported, with the most common symptoms including CNS depression, serotonin toxicity, seizures, or cardiac conduction disturbances. The toxicity of Velaxin appears to be greater than that of other SSRIs, and the lethal toxic dose is closer to that of tricyclic antidepressants than to SSRIs. Doses of 900 mg or more are likely to cause moderate toxicity. Deaths have been reported only after taking very large doses. Plasma concentrations of Velaxin during overdose in survivors range from 6 to 24 mg/L, while levels leading to fatalities are often in the range of 10-90 mg/L. On 31 May 2006, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) completed its review of the latest safety data relating to Velaxin and in particular the risks associated with overdose. They suggest the need for specialist supervision in cases of severe depression or hospitalization for patients who require a dose of 300 mg or more; cardiac contraindications are more focused on high-risk groups; patients with uncontrolled hypertension should not take Velaxin and regular blood pressure monitoring is recommended for all patients; In addition, it is necessary to monitor updated recommendations regarding possible drug interactions. On October 17, 2006, Wyeth and the FDA notified health care professionals of changes to the overdose/human study information for the drug Effexor (Velaxin) for the treatment of major depressive disorder. During post-marketing research, there have been reports of Velaxin overdose, mainly in combination with alcohol and/or other drugs. Published retrospective studies suggest that overdose with Velaxin may be associated with an increased risk of death compared with SSRI antidepressants, and a reduced risk compared with tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest number of capsules possible and monitor the patient closely throughout treatment to reduce the risk of overdose. An article published in 2002 in the British Medical Journal by Dr. Nicholas Buckley and colleagues from the Department of Clinical Pharmacology and Toxicology at Canberra Hospital, Australia, who studied the fatal toxicity index (deaths per million prescriptions) suggests that the fatal toxicity of Velaxin is higher than that of Velaxin. than the toxicity of other serotonergic antidepressants, but similar to some of the less toxic tricyclic antidepressants. Overall, scientists say there is a serious risk of toxicity from an overdose of Velaxin, with reports of death, arrhythmias and seizures. They argue, however, that these data are open to criticism, noting that mortality data may be influenced by previous data and that "less toxic" drugs may be prescribed predominantly to patients at high risk of poisoning and suicide, but are also less likely to should be reported as the sole cause of overdose death. It is also assumed that drugs in case of overdose are taken with the same frequency and in equal quantities. The scientists suggest that "clinicians consider all factors in their patients that reduce or offset these risks before prescribing Velaxin." On February 27, 2007, the Vancouver Sun reported that the BC Drug and Poison Information Center issued a warning to doctors that the drug poses a significant risk of overdose death, stating that Velaxin "is more toxic than originally thought." A physician in the Department of Pharmacy Services, College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina, reported the death of a 39-year-old patient from a 30-g overdose. To understand what we're talking about, imagine if a patient were to take 66 infrequently prescribed high-dose 450 mg tablets, or 400 commonly prescribed 75 mg tablets.

Special instructions for the use of the drug Velaxin

In patients with depression, the likelihood of suicide attempts should be considered before starting any therapy. Therefore, to reduce the risk of overdose, the initial dose of the drug should be as low as possible, and the patient should be under medical supervision. Aggressive behavior of the patient has been reported during the use of venlafaxine (especially at the beginning of the course of treatment and after discontinuation of the drug). The use of venlafaxine is associated with the development of psychomotor agitation, which is characterized by subjectively unpleasant restlessness with a need to move. Most often this occurs during the first weeks of treatment. If such symptoms occur, increasing the dose may not be appropriate, so the question of whether it is advisable to continue taking venlafaxine should be decided. In patients with mood disorders, hypomanic or manic states may occur when treated with antidepressants, including venlafaxine. Velaxin should be prescribed with caution to patients with a history of mania. These patients require medical supervision. Velaxin should be prescribed with caution to patients with a history of epileptic seizures. If epileptic seizures occur, treatment must be stopped. The patient should be warned about the need to immediately consult a doctor if a skin rash, elements of urticaria or other allergic reactions occur. In some patients, during the period of use of venlafaxine, a dose-dependent increase in blood pressure is possible, and therefore it is recommended to regularly monitor blood pressure, especially during the period of dose adjustment or increase. An increase in heart rate is possible, especially when taken in high doses. In this case, medical supervision of the patient's condition is necessary. Occasionally, orthostatic hypotension was observed during use of the drug. Patients, especially the elderly, should be warned about the possibility of dizziness. Velaxin may increase the risk of hemorrhages in the skin and mucous membranes in patients predisposed to these conditions. Patients should be warned about this and advised to exercise caution while using the drug. During the use of Velaxin, especially in conditions of dehydration or decrease in blood volume (including in elderly patients and in patients taking diuretics), hyponatremia and/or syndrome of insufficient secretion of antidiuretic hormone is possible. During the period of use of the drug, mydriasis may occur, and therefore it is recommended to monitor intraocular pressure in patients with a tendency to increase it, in patients with angle-closure glaucoma. When treating patients with impaired renal or hepatic function, caution and careful medical monitoring of the patient's condition is necessary (dose reduction is possible). In patients who have recently suffered a myocardial infarction and with signs of decompensated heart failure, the drug should be prescribed with caution under constant medical supervision. The safety and effectiveness of the combined use of venlafaxine and drugs used for weight loss, including phentermine, have not been established, so their simultaneous use is not recommended. With prolonged use of the drug, it is advisable to monitor the level of cholesterol in the blood serum. After stopping the use of Velaxin, especially suddenly, withdrawal syndrome often occurs. The risk of developing withdrawal syndrome depends on the duration of treatment, the dose used, and the rate of dose reduction. With withdrawal syndrome, dizziness, paresthesia, sleep disturbance, agitation, anxiety, nausea, vomiting, tremor, sweating, headache, diarrhea, tachycardia, and emotional disorders appear. These symptoms are usually observed in the first days after discontinuation of the drug and disappear on their own within 2 weeks. Therefore, the drug should be discontinued gradually, reducing the dose of venlafaxine gradually over several weeks or months, depending on the patient's condition. Velaxin does not cause the development of symptoms of tolerance or dependence. Despite this, as with other drugs that act on the central nervous system, patients need to be monitored for signs of drug abuse (especially patients with a history of similar problems). While using Velaxin, women of reproductive age should use adequate methods of contraception. The drug may negatively affect the ability to drive vehicles and operate potentially dangerous machinery. Therefore, doses at which driving vehicles and working with machinery are possible are determined for each patient individually.

Instructions for use VELAXIN® tablets

Suicide/suicidal ideation or clinical worsening

Depression is associated with an increased risk of suicidal ideation, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. Since improvement may not occur during the first few weeks of treatment or longer, patients should be closely monitored until such improvements occur. Clinical experience suggests a possible increased risk of suicide in the early stages of remission.

Other psychiatric conditions for which venlafaxine is prescribed may also be associated with an increased risk of suicidal events. In addition, these conditions may be comorbid with major depressive disorder. The precautions observed when treating patients with major depressive disorder should also be observed when treating patients with other psychiatric disorders.

It is known that patients with a history of suicidal symptoms who exhibit a significant degree of suicidal ideation before treatment are at greater risk of suicidal ideation and suicide attempts; During treatment, such patients should be closely monitored. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behavior in patients under 25 years of age taking antidepressants compared with age-matched patients taking placebo.

Patients, incl. those at high risk of suicidal ideation and suicide attempts require careful monitoring during drug treatment, especially at the beginning of treatment and when changing doses. Patients (and caregivers) should be warned to monitor for clinical worsening, suicidal behavior or ideation, or unusual changes in behavior, and to seek prompt medical attention if these symptoms occur.

Use in children and adolescents under 18 years of age.

Velaxin® immediate release tablets should not be used to treat children and adolescents under 18 years of age. Suicidal behavior (suicide attempt and suicidal ideation) and hostility (primarily aggression, hostile behavior and anger) were observed more frequently in children and adolescents treated with antidepressants compared with those taking placebo in clinical studies. If, despite this, a decision is made to carry out treatment, careful monitoring of the patient is necessary in order to identify suicidal symptoms. In addition, there are no long-term safety data on growth, maturation, and cognitive and behavioral development in children and adolescents.

Serotonin syndrome

As with other serotonergic drugs, venlafaxine may cause serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions, a potentially life-threatening condition, particularly when co-administered with other serotonergic drugs (including triptans, serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), amphetamines, lithium preparations, sibutramine, preparations containing St. John's wort ( Hypericum perforatum

), fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with drugs that inhibit serotonin metabolism (MAO inhibitors, such as methylene blue), with serotonin precursors (for example, with supplements containing tryptophan), and also with other antipsychotic drugs and dopamine antagonists (see sections Contraindications and Drug Interactions).

Serotonin syndrome may include the following symptoms:

• mental status changes (eg, psychomotor agitation, hallucinations, coma), autonomic nervous system disturbance (eg, tachycardia, unstable blood pressure, hyperthermia), neuromuscular disturbances (eg, hyperreflexia, incoordination), and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea).

In its most severe form, serotonin syndrome is similar to NMS, with symptoms such as hyperthermia, muscle rigidity, instability of the autonomic nervous system with possible rapid changes in the patient's vital signs and mental status.

If there is a clinical need for the combined use of venlafaxine with other drugs that affect the serotonergic or dopaminergic neurotransmitter system, it is recommended to carefully monitor the patient's condition, especially at the beginning of treatment and when increasing doses.

Concomitant use of venlafaxine with serotonin precursors (eg, tryptophan-containing supplements) is not recommended.

Narrow-angle glaucoma

Mydriasis may occur in connection with taking venlafaxine. Close monitoring of patients with elevated intraocular pressure or patients at risk of developing angle-closure glaucoma is recommended.

Arterial pressure

A dose-dependent increase in blood pressure is often reported when taking venlafaxine. In the post-marketing period, several cases of severe increases in blood pressure requiring immediate treatment have been observed. Before starting treatment, all patients should undergo a thorough evaluation for high blood pressure, and control of pre-existing hypertension is also necessary. Periodic monitoring of blood pressure is necessary after starting treatment, as well as after increasing the dose. Caution should be exercised when prescribing the drug to patients whose underlying disease may be accompanied by an increase in blood pressure, for example, with impaired cardiac function.

Heartbeat

An increase in heart rate is possible, especially when taking the drug in high doses. Caution should be exercised when prescribing the drug to patients in whom an increase in heart rate may have an adverse effect on the underlying disease.

Heart disease and risk of arrhythmia

There is insufficient experience with the use of venlafaxine in patients who have recently had a myocardial infarction or have unstable cardiac disease. Therefore, it should be used with caution in such patients. In the post-marketing period, cases of QTc prolongation, torsade de pointes (TdP), torsade de pointes (TdP), and fatal cardiac arrhythmias have been observed with venlafaxine, especially in overdose or in patients with risk factors for QTc prolongation or torsade de pointes (see Pharmacology). action). The risk-benefit ratio must be assessed before prescribing venlafaxine to patients at high risk of serious cardiac arrhythmias (see Pharmacological Actions).

Convulsions

During treatment with venlafaxine, seizures may occur. As with all antidepressants, venlafaxine should be used with caution in patients with a history of seizures; such patients should be closely monitored. Treatment with the drug should be discontinued in patients who develop seizures.

Hyponatremia

When taking venlafaxine, cases of hyponatremia and/or syndrome of impaired antidiuretic hormone secretion are possible. This phenomenon was most often observed in patients with hypovolemia or dehydration. Elderly patients, patients taking diuretics, and patients at increased risk of hypovolemia are at greater risk for this phenomenon.

Abnormal bleeding

Medicines that inhibit serotonin reuptake may lead to decreased platelet function. Patients taking SSRIs and SNRIs, including venlafaxine, may have an increased risk of bleeding, ranging from ecchymoses, hematomas, epistaxis and petechiae to gastrointestinal and life-threatening bleeding. Patients receiving venlafaxine may have an increased risk of bleeding. As with other serotonin reuptake inhibitors, venlafaxine should be administered with caution to patients predisposed to bleeding, including patients taking anticoagulants and platelet inhibitors.

Serum cholesterol

In placebo-controlled clinical studies, a clinically significant increase in serum cholesterol was observed in 5.3% of patients receiving venlafaxine and 0.0% of patients receiving placebo for at least 3 months. With long-term use of the drug, it is advisable to monitor the cholesterol level in the blood serum.

Combined use with weight loss agents

Safety and effectiveness of combining venlafaxine with weight loss agents, incl. phentermine, not established. It is not recommended to use venlafaxine and weight loss agents together. Venlafaxine should not be used as a means of weight loss and is not recommended in combination with other drugs.

Mania/hypomania

In a small number of patients with mood disorders receiving antidepressants, incl. and venlafaxine, mania/hypomania may occur. As with other antidepressants, venlafaxine should be prescribed with caution to patients with a personal or family history of bipolar affective disorder.

Aggression

In a small number of patients during treatment with antidepressants, incl. venlafaxine, aggression may occur. These symptoms were observed at the beginning of treatment, with increasing doses and discontinuation of treatment.

As with other antidepressants, venlafaxine should be prescribed with caution to patients with a history of aggression.

Stopping treatment

After stopping treatment (especially abruptly), withdrawal symptoms often appear (see section Side effects). In clinical studies, adverse events observed after treatment discontinuation (dose taper and post-dose reduction) occurred in approximately 31% of patients receiving venlafaxine and 17% of patients receiving placebo.

The risk of withdrawal symptoms may depend on several factors, including: on the duration of treatment and doses used, as well as the rate of dose reduction. Dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), psychomotor agitation or anxiety, nausea and/or vomiting, tremor and headache are the most common reactions. In general, these symptoms are mild or moderate, however, in some patients they can be severe.

Typically, symptoms appear within the first few days after stopping treatment, but in very rare cases, similar symptoms have been reported in patients who accidentally missed a dose. These symptoms usually go away on their own, usually within 2 weeks, but in some patients they may persist for a longer period of time (2-3 months or more). Therefore, if it is necessary to discontinue treatment, it is recommended to gradually reduce the dose (over several weeks or months, depending on the patient's response (see Dosage Regimen).

Akathisia/psychomotor restlessness

The use of venlafaxine is associated with the development of akathisia, characterized by a subjectively unpleasant and disturbing restlessness for the patient, with a need to move, often combined with the inability to sit or stand still. This is most likely to occur during the first few weeks of treatment. In patients with such symptoms, increasing the dose may have an adverse effect.

Dry mouth

Dry mouth occurs in 10% of patients receiving venlafaxine. This may increase the risk of dental caries and patients should be advised of the importance of dental hygiene.

Diabetes

In patients with diabetes mellitus, the use of selective serotonin reuptake inhibitors or venlafaxine may lead to changes in glycemic control. It may be necessary to change the dose of insulin and/or oral antidiabetic medications.

Sexual dysfunction

SSRIs and SNRIs can cause sexual dysfunction. There have been reports of long-term impairment of sexual function despite discontinuation of SSRIs or SNRIs.

Impact on the results of laboratory tests for the presence of narcotic drugs

False-positive urine immunoassay results for phencyclidine (PCP) and amphetamine have been observed in patients receiving venlafaxine. This is due to the lack of specificity of immunotests. False-positive test results are possible several days after venlafaxine is discontinued. Confirmatory tests such as gas chromatography or mass spectrometry can differentiate venlafaxine from phenylcyclidine and amphetamine.

Velaxin® tablets contain lactose

Patients with rare hereditary diseases such as galactose intolerance, complete lactase deficiency and glucose/galactose malabsorption should not take this drug.

Sodium content

All Velaxin® tablets with varying levels of active substance contain less than one millimole (23 mg) of sodium, so the tablets are practically sodium-free.

Preclinical safety studies

Studies of venlafaxine in rats and mice showed no evidence of tumorigenesis. In numerous in vitro

and
in vivo
, venlafaxine demonstrated no mutagenicity.

Reproductive toxicity studies in animals have shown decreased body weight of pups, increased rates of stillborn pups, and increased pup mortality during the first 5 days of lactation. The cause of these deaths is unknown. These effects were observed at a dose of 30 mg/kg/day, which is 4 times higher than the daily dose of venlafaxine for humans - 375 mg (based on mg/kg). The dose at which these effects were absent is 1.3 times the human dose. The potential risk to humans is unknown.

Decreased fertility was observed in a study in which both male and female rats were given EFA. The dose administered in this case was approximately 1-2 times higher than the human dose of 375 mg/day. The clinical significance of this interaction is unknown.

Impact on the ability to drive vehicles and operate machinery

Any psychotropic drug can affect thinking, judgment and motor skills. Therefore, patients receiving venlafaxine should be warned about the possible effect of the drug on their ability to drive vehicles or operate dangerous machinery.

Interactions of the drug Velaxin

The use of Velaxin in combination with MAO inhibitors is contraindicated: tremor, myoclonus, sweating, nausea, vomiting, flushing, dizziness, fever, convulsive seizures, and death are possible. The use of Velaxin can be started no earlier than 14 days after the end of MAO inhibitor therapy. If a reversible MAO inhibitor is used, this interval may be shorter (24 hours). After discontinuation of Velaxin, you should take a break of at least 7 days before starting therapy with MAO inhibitors. Particular caution is required when using Velaxin with drugs that affect the central nervous system. The mutual influence of Velaxin and the following drugs should be taken into account: Lithium: there are reports of interaction between lithium and venlafaxine, as a result of which the level of lithium in the blood increases. Imipramine: the pharmacokinetics of venlafaxine and its metabolite EDV do not change, so a dose reduction of venlafaxine is not required when these drugs are used in combination. Haloperidol: its effect may be enhanced. Diazepam: the pharmacokinetics of the drugs and their main metabolites do not change significantly. Clozapine: an increase in the level of clozapine in the blood and the development of its side effects (for example, epileptic seizures) were noted. Risperidone: with the simultaneous use of these drugs (despite the increase in the AUC of risperidone), the pharmacokinetics of the sum of the active components (risperidone and its active metabolite) does not change significantly. Alcohol: depression of psychomotor activity under the influence of alcohol after taking venlafaxine does not increase, however, during the period of use of the drug Velaxin, the consumption of alcoholic beverages is not recommended. Electroconvulsive therapy: when conducting electroconvulsive therapy while taking selective inhibitors of neuronal reuptake of serotonin, an increase in the duration of epileptic activity was noted. It is necessary to exercise caution and ensure careful medical monitoring of the patient's condition when combined with this type of therapy and the use of Velaxin. Drugs metabolized by cytochrome P450 isoenzymes : the CYP 2D6 enzyme of the cytochrome P450 system converts venlafaxine into the active metabolite EDV. Unlike many other antidepressants, the dose of Velaxin does not need to be reduced when used once with drugs that inhibit CYP 2D6 activity, or in patients with a genetically determined decrease in CYP 2D6 activity, since the total concentration of the active substance and metabolite (venlafaxine and ODV) does not change. The main route of elimination of venlafaxine involves metabolism with the participation of CYP 2D6 and CYP 3A4, so special caution should be exercised when prescribing venlafaxine in combination with drugs that inhibit both of these enzymes. Venlafaxine is a relatively weak inhibitor of CYP 2D6 and does not inhibit the activity of CYP 1A2, CYP 2C9 and CYP 3A4 isoenzymes; therefore, it should not be expected to interact with other drugs in which these liver enzymes are involved in the metabolism. Cimetidine: inhibits the metabolism of venlafaxine during its initial passage through the liver, but does not have a significant effect on its conversion to EDV or the rate of elimination of EDV, the concentration of which in the circulating blood is much higher. Therefore, there is no need to change the dose of Velaxin and cimetidine when used in combination. This interaction may be more pronounced in elderly patients or with impaired liver function, therefore, in such cases, the combined use of cimetidine and Velaxin requires medical supervision. Antihypertensive and antidiabetic agents: no clinically significant interactions of venlafaxine with antihypertensive (including beta-adrenergic receptor blockers, ACE inhibitors and diuretics) and hypoglycemic agents have been identified. Drugs that bind to plasma proteins: Plasma protein binding is 27% for venlafaxine and 30% for EDV. Therefore, interactions due to their binding to proteins should not be expected. Warfarin: the anticoagulant effect of the latter may be enhanced; at the same time, prothrombin time increases. Indinavir: When used concomitantly with this drug, the pharmacokinetics of indinavir changes (with a 28% decrease in AUC and a 36% decrease in maximum concentration).

Velaxin®

Concomitant use of monoamine oxidase inhibitors (MAO)

and venlafaxine is contraindicated. Taking Velaxin® can be started no less than 14 days after the end of therapy with MAO inhibitors. If a reversible MAO inhibitor (moclobemide) was used, this interval may be shorter (24 hours). Therapy with MAO inhibitors can be started no less than 7 days after discontinuation of Velaxin®.

Venlafaxine does not affect the pharmacokinetics of lithium

.

When used simultaneously with imipramine

m, the pharmacokinetics of venlafaxine and its metabolite O-desmethylvenlafaxine (ODV) do not change.

Haloperidol

: the effect of the latter may be enhanced due to an increase in the level of the drug in the blood when used together.

When used simultaneously with diazepam

the pharmacokinetics of drugs and their main metabolites do not change significantly. There was also no effect on the psychomotor and psychometric effects of diazepam.

When used simultaneously with clozapine

There may be an increase in its level in the blood plasma and the development of side effects (for example, epileptic seizures).

When used simultaneously with risperidone

(despite the increase in AUC of risperidone), the pharmacokinetics of the sum of the active components (risperidone and its active metabolite) did not change significantly.

Increases the effects of alcohol

on psychomotor reactions.

While taking venlafaxine, special caution should be exercised during electroconvulsive therapy.

, since there is no experience with the use of venlafaxine in these conditions.

Drugs metabolized by cytochrome P 450 isoenzymes

:

The enzyme CYP2D6 of the cytochrome P 450 system converts venlafaxine into the active metabolite O-desmethylvenlafaxine (ODV). Unlike many other antidepressants, the dose of venlafaxine does not need to be reduced when administered simultaneously with drugs that inhibit CYP2D6 activity, or in patients with a genetically determined decrease in CYP2D6 activity, since the total concentration of the active substance and metabolite (venlafaxine and EDV) will not change.

The main route of elimination of venlafaxine involves metabolism by CYP2D6 and CYP3A4; therefore, special caution should be exercised when prescribing venlafaxine in combination with drugs that inhibit both of these enzymes. Such drug interactions have not yet been studied.

Venlafaxine is a relatively weak inhibitor of CYP2D6 and does not suppress the activity of the CYP1A2, CYP2C9 and CYP3A4 isoenzymes; therefore, it should not be expected to interact with other drugs that are metabolized by these liver enzymes.

Cimetidine

suppresses the “first pass” metabolism of venlafaxine and does not affect the pharmacokinetics of O-desmethylvenlafaxine. In most patients, only a slight increase in the overall pharmacological activity of venlafaxine and O-desmethylvenlafaxine is expected (more pronounced in elderly patients and with impaired liver function).

Clinically significant interactions of venlafaxine with antihypertensive (including beta blockers, ACE inhibitors and diuretics) and antidiabetic drugs

not detected

Drugs bound to plasma proteins

: Plasma protein binding is 27% for venlafaxine and 30% for EDV. Therefore, it does not affect the concentration of drugs in the blood plasma that have a high degree of protein binding.

When taken simultaneously with warfarin

the anticoagulant effect of the latter may be enhanced.

When taken simultaneously with indinavir

the pharmacokinetics of indinavir changes (with a 28% decrease in the area under the AUC curve and a 36% decrease in the maximum concentration Cmax), and the pharmacokinetics of venlafaxine and EDV do not change. However, the clinical significance of this effect is unknown.

Velaxin overdose, symptoms and treatment

Symptoms: ECG changes (increased QT , bundle branch block, expansion of the QRS ), sinus and ventricular tachycardia, bradycardia, hypotension, convulsions, impaired consciousness. In some cases, fatalities due to overdose have been reported when high doses of venlafaxine were taken concomitantly with alcohol and/or other psychotropic drugs. Treatment: there is no specific antidote. Gastric lavage and the use of activated carbon are indicated. Inducing vomiting is not recommended. It is necessary to ensure airway patency, adequate ventilation and oxygenation. Monitoring of ECG and vital body functions is recommended, as well as supportive and symptomatic therapy. In case of overdose, the possibility of the patient taking several psychotropic drugs simultaneously should be taken into account. Venlafaxine and EDV are not eliminated by dialysis.

Venlafaxine (Velaxin) - the most effective antidepressant?

Summary

Evidence-based medicine has failed to provide convincing evidence that antidepressants differ in their effectiveness in treating depression. Therefore, scientists base their judgments about the effectiveness of drugs on “personal experience.” There is another way to determine the most effective antidepressant. To do this, it is necessary to compare data on the activity of neurons in depression and the ability of antidepressants to affect these neurons. This comparison suggests that the most effective antidepressants are amitriptyline, imipramine and venlafaxine (in high daily doses). But only venlafaxine is used in our country in therapeutic doses. Therefore, venlafaxine is the most effective antidepressant.

Persistent attempts by pharmaceutical companies, using evidence-based medicine, to confirm that their antidepressant is the most effective in treating depression have so far been unsuccessful. Not only individual critics of such studies agree with this, but also large teams of scientists who draw up recommendations for the pharmacotherapy of depressive disorders. In any case, they proceed from the fact that evidence-based medicine indicates comparable activity of antidepressants in the treatment of depression (1, 2, 3). Therefore, to determine the most effective drugs, scientists resort to the “personal experience” accumulated during the treatment of patients (4), which is always subjective. This method of determining the most effective antidepressants is vulnerable to criticism. An alternative to “personal experience” is to compare the mechanisms of depression formation (pathogenesis) and the medicinal properties of drugs.

It is known that symptoms of depression are accompanied by a decrease in the activity of various neurons: norepinephrine (↓N), dopamine (↓D), serotonin (↓C) and melatonin (↓M) (Table 1).

Table 1. Reduced neuronal activity in different symptoms of depression (5, 6, 7).

The main of these symptoms, reflecting deterioration (decrease) in mood (3, 6), are associated with deterioration in the functioning of norepinephrine and dopamine (↓ND), norepinephrine and serotonin (↓SN), as well as serotonin, norepinephrine and dopamine neurons (↓SND). Accordingly, all depressions can be divided into three classes. The first of these includes ↓ND depression. They occur with a weakening of positive emotions. The second option covers ↓HF depression. They are characterized by increased negative emotions. Finally, the third one includes ↓SUD-depression. They are accompanied by both a weakening of positive and an increase in negative emotions. With all three of these types of depression, phenomena of psychomotor retardation (↓H-symptoms) and/or somatic symptoms (↓SND or ↓SUI) may be observed. From the presented data it follows that for the successful treatment of any depression it is necessary to increase the activity, first of all, of norepinephrine, dopamine and serotonin neurons (↑SND). Accordingly, this is exactly how the most effective antidepressants should act. In other words, they must be ↑SND drugs.

To increase the activity of serotonin, norepinephrine and dopamine neurons, antidepressants have only three mechanisms. They can be neurotransmitter reuptake inhibitors (NRRIs), agents affecting regulatory receptors (ARRIs), or drugs that reversibly inhibit monoamine oxidase type A (MAO-A) (Table 2).

Table 2. Antidepressants known in Russia, their effect on neurons and the “formula” of the mechanism of action (4, 5, 6, 8).

*- white color – the drug does not affect neurons, dark gray – a pronounced increase in activity, light gray – a moderate increase in activity,

**- in high doses

However, the overwhelming majority of antidepressants used in Russia are classified as IOPs (Table 2). It is this pharmacological property that determines the ability to activate neurons in 66.7% of drugs related to tricyclic (TCA) and quadricyclic (TCA) antidepressants, as well as selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) . Three more drugs (14.3%) combine the properties of IOP and SVRR. Trazodone (serotonin modulating antidepressant - SMA), milnacipran (SNRI) and vortioxetine (multimodal antidepressant - MMA) have such a mixed mechanism of action.

A similar situation is observed throughout the world. Most antidepressants are IODs. For example, in the United States, these include 8 of the 10 most commonly prescribed drugs (duloxetine, desvenlafaxine, citalopram, setralin, fluoxetine, escitalopram, paroxetine, venlafaxine) (9). Another one, vilazodone, combines the property of an IOP with a different mechanism of action. In some countries (for example, in the USA), the reputation of IOPs is so high that they try not to register antidepressants that do not have this mechanism of action at all (10).

IOHs are not only allowed into the medical services market as a priority, but they are also considered a kind of “standard”. After all, their mechanism of action leaves neurotransmitters (serotonin, norepinephrine or dopamine) where they usually realize their effects - “between” neurons in the so-called. “intersynaptic gap” (5). As a result, serotonin, norepinephrine, or dopamine act on nerve cells for a longer time, and neurons fire more than usual. It is also important that this mechanism of action is completely reversible, since it does not promote the creation of new neurotransmitters (their synthesis) and does not inhibit their breakdown (metabolism). And this is very important for the safety of treatment.

But not all antidepressants are strong IODs (4, 5). For some drugs, this mechanism of action is much less pronounced (Table 2). Thus, pipofesin (TcA), which is indicated only for mild to moderate depression (11), most likely moderately activates serotonin, norepinephrine and dopamine neurons. Trazodone (SmA) and vortioxetine (MmA) are serotonin IODs (Table 2). But this mechanism of action is less pronounced in them compared to SSRIs (4, 12).

Antidepressants may be strong SRIs only for serotonin (SSRI: sertraline, paroxetine, citalopram, escitalopram, fluoxetine, fluvoxamine, TCA: clomipramine), norepinephrine (SA: maprotiline; SNRI: milnacipran) or both of these neurotransmitters (TCA: amitriptyline, imipramine; SNRIs: venlafaxine and duloxetine) (4, 5, 13, 14). With regard to dopamine, all modern drugs are only weak IOPs (TCA: amitriptyline, imipramine, clomipramine, pipofezin; SNRIs: venlafaxine in high daily doses), or do not act at all on the metabolism of this neurotransmitter (4, 5, 6, 13, 14) . In addition, for some IODs, the potential to affect different nerve cells is dose dependent (7).

Thus, venlafaxine (SNRI), especially in low daily doses (75-150 mg), is more of a serotonin IOI and affects serotonin neurons. At the same time, it has an active metabolite, desvenlafaxine. This substance is itself an antidepressant abroad, and its properties differ from venlafaxine. Desvenlafaxine is a strong IOR of serotonin and norepinephrine, and in high doses is a weak IOR of dopamine. The amount of desvenlafaxine is considered to be half the prescribed daily dose of venlafaxine. As the dosage of the latter increases, the concentration of its active metabolite in the blood also increases. Accordingly, venlafaxine, prescribed at a dose of 150-225 mg/day, due to desvenlafaxine is converted into an IOP of serotonin and norepinephrine. As a result, it effectively activates serotonin and norepinephrine neurons (Table 2). If the daily dose is increased further, then venlafaxine (together with desvenlafaxine) will acquire the properties of dopamine IOZ. Then the drug will activate not only serotonin and norepinephrine neurons, but also dopamine neurons, although much weaker (Table 2).

Moving now to SVRR (mianserin - ChsA, mirtazapine - norepinephrine and selective serotonin antidepressant - NaSSA, agomelatine - melatonergic antidepressant) we will point out the reason why they are inferior, at least to strong IOs, in the effectiveness of their action on neurons (Table 2 ). With the help of RR, it is not the excitation of nerve cells that is carried out, but rather the “fine-tuning” of their “tone” (5, 8, 15). Therefore, “pure” SVRRs are quite rare among antidepressants.

But there are many IOPs whose effect on RR is an additional mechanism of action. But due to its relative weakness, it is not even mentioned in drug instructions (16, 17, 18). For example, milnacipran (SNRI) is a serotonin and norepinephrine SRI (16). This property gives the antidepressant the ability to effectively activate norepinephrine neurons and, more weakly, serotonin neurons (6). At the same time, milnacipran, due to its effect on RR, promotes a moderate increase in the “tone” of dopamine nerve cells (19). However, this property is not mentioned in the instructions for the drug. And only for some IOIs the effect on RR is still mentioned in the guidelines for the medical use of antidepressants. This feature is characteristic of trazodone (SmA) and vortioxetine (MmA) (5, 8, 20). Both antidepressants are serotonin IRIs. This property allows them to moderately activate serotonin neurons (Table 2). And due to their effect on RR, they slightly increase the “tone” of norepinephrine and dopamine nerve cells.

Finally, two more drugs (OIMAO-A: pirlindole and moclobemide) to activate neurons depress (inhibit) the work of the enzyme - monoamine oxidase, which destroys neurotransmitters (serotonin, norepinephrine, dopamine) (5, 20, 21, 22, 23), as inside neurons and outside them - in the intersynaptic cleft. It would seem that this mechanism of action should be very strong, because as a result, the amount of serotonin, norepinephrine and dopamine increases both inside and outside the neuron. However, this effect is typical primarily for the so-called. irreversible monoamine oxidase inhibitors that form stable chemical bonds with this enzyme (24). After this, it can no longer perform its functions and disintegrates, and instead the body is forced to synthesize a new enzyme, which usually takes about two weeks. As a result, irreversible monoamine oxidase inhibitors are indeed highly active antidepressants. However, due to the high efficiency of their mechanism of action, they are poorly tolerated and can even be toxic, and their use in our country has practically ceased.

A different picture is observed in the case of pirlindole and moclobemide (20, 22). The effect of these drugs on the enzyme is reversible (MAOI). The fact is that their connection with the enzyme is only relatively stable. Its gradual disappearance leads to the release of monoamine oxidase, while the enzyme itself remains intact (24). In addition, pirlindole and moclobemide selectively inhibit the activity of only one of the types of monoamine oxides - “A” (OMAO-A), while the other type “B” continues to work almost with the same strength. All these features significantly reduce the effectiveness of OIMAO-A, which is why the mechanism of action under consideration is much less common than IOI (Table 2). At the same time, these features make OIMAO-A more tolerable drugs that weakly activate serotonin, norepinephrine and dopamine neurons.

The presented features of the mechanisms of action of antidepressants can be represented in the form of a letter formula consisting of the first letters of the name of the neuron on which it acts (↑с, ↑н, ↑н, ↑м). Moreover, in the case of pronounced activation of the nerve cell, you can use a capital letter (↑С, ↑Н, ↑Д, ↑М), and in case of weak activation, a lowercase letter (↑с, ↑н, ↑д, ↑м). An individual “formula” of the mechanism of action of an antidepressant is obtained (hereinafter simply “formula”), which reflects its pharmacological activity much more accurately than the name of the group.

Such “formulas” indicate the existence of “triple” action drugs. These include:

• ↑SNd antidepressants (active effect on serotonin and norepinephrine neurons and weaker on dopamine neurons): amitriptyline (TcA),
• Imipramine (TCA)
• venlafaxine (SNRI) in high daily doses

There are drugs with “dual” action. These include:

• ↑SN-antidepressants (active effect on serotonin and norepinephrine neurons): duloxetine (SNRI)
• venlafaxine (SNRI) in average daily doses

Finally, “single” action drugs include:

• ↑C-antidepressants (active effect on serotonin neurons): sertraline (SSRI),
• paroxetine (SSRI),
• citalopram (SSRI),
• escitalopram (SSRI),
• fluoxetine (SSRI),
• fluvoxamine (SSRI).

The presented data makes it easy to determine that the most effective will be “triple” action antidepressants, whose formula contains the largest number of capital letters. These are ↑SNd antidepressants that actively affect serotonin and norepinephrine neurons and weaker on dopamine neurons: amitriptyline (TcA), imipramine (TcA), venlafaxine (SNRI) in high daily doses. This set of pharmacological properties allows them to influence all three types of depression (↓ND with weakening of positive emotions; ↓CH with increased negative emotions; ↓SND-depression with weakening of positive and increased negative emotions), which can be accompanied by symptoms of psychomotor retardation (↓ H-symptoms) and/or somatic symptoms (↓SND or ↓SUM).

The presented very short list of the most effective antidepressants correlates well with the “personal experience” of foreign experts creating recommendations. It was already mentioned above that TCA and SNRIs are recognized as the most powerful drugs there (4). Some recommendations contain more precise instructions. It reports that, along with TCAs, only one SNRI, venlafaxine, is the most effective (3). But experts always make a reservation that they cannot provide any objective evidence of their point of view. One can only regret that they did not want to address the peculiarities of the formation of symptoms of depression and the mechanism of action of antidepressants. If we take into account the relationships between them, then the “personal experience” of experts becomes quite understandable and even “public.”

The analysis performed puts venlafaxine in an exceptional position, especially in our country. It is well known that in Russia TCAs (amitriptyline and imipramine) are prescribed very “sparingly” in low doses, which, as a rule, are less than therapeutic ones (25, 26). This is due to the pronounced side effects characteristic of amitriptyline and imipramine. Meanwhile, any drug, including TCA, when prescribed in doses that do not reach the therapeutic range, loses its effectiveness. As a result, in our country only venlafaxine can claim to be the most effective antidepressant. And this drug is widely used in our country in the form of Velaxin (Egis). It was recommended by leading scientific organizations conducting advanced research in the field of psychiatry. Among them are the Federal State Budgetary Institutions “State Scientific Center for Social and Forensic Psychiatry named after V.P. Serbsky" and "Moscow Research Institute of Psychiatry" of the Russian Ministry of Health, St. Petersburg Research Institute named after. V.M. Bekhterev (27, 28). Long-acting capsules (Velaxin retard) are also well known (29), with the use of which there is a significant reduction in the frequency of such side effects of the drug as nausea (30). In addition, the study of Velaxin was successfully carried out not only in psychiatry, but also in neurology (31). It remains to be recommended to use this antidepressant as widely as possible in the treatment of depression.

A video by M.Yu. Drobizhev on the same topic can be viewed at the link:

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M.Yu. Drobizhev, Doctor of Medical Sciences, Head of the Educational Department of the Educational Center of the Association of Medical and Pharmaceutical Universities of Russia

Contact Information -

E.Yu. Antokhin, Candidate of Medical Sciences, Associate Professor, Head of the Department of Clinical Psychology and Psychotherapy of the Orenburg State Medical University of the Russian Ministry of Health.

R.I. Palaeva is an assistant at the Department of Clinical Psychology and Psychotherapy at the Orenburg State Medical University of the Russian Ministry of Health.

S. V. Kikta, Candidate of Medical Sciences, Head. Department of the Federal State Budgetary Institution "Polyclinic No. 3" of the Administration of the President of the Russian Federation, Moscow