Venlafaxine adverse effects

The aim of the study was to evaluate the clinical effect of venlafaxine during course treatment of patients with various depressive states of endogenous nature.

Material and methods

We examined 32 patients, 15 women and 17 men, aged 18 to 57 years (mean age 31.75 years) with endogenous depression, who underwent inpatient treatment in the clinical departments of the Department for the Study of Endogenous Mental Disorders and Affective States of the Federal State Budgetary Institution Scientific Center for Mental health" RAS.

The study was open naturalistic in design. The average duration of the disease from its first manifestation was 7.9 years, the average number of depressive episodes transferred before inclusion in the study was 3.3. The duration of the current depressive episode prior to Velaxin was on average 4.5 months.

According to the nosological affiliation, the patients were distributed as follows: 22 (68.6%) patients were diagnosed with endogenous affective diseases - manic-depressive psychosis (MDP), cyclothymia; in 5 (15.6%) depression developed in the dynamics of low-progressive schizophrenia, and in 5 (15.6%) there was post-psychotic depression in the framework of paroxysmal schizophrenia. According to ICD-10, the depressive state of patients was diagnosed according to the following headings: F31.3—F31.4; F32.0-F32.2; F33.0-F33.2; F21; F20.4. Typologically, depressive states were defined as melancholy (3 patients, 9.4%), anxious (11 cases; 34.4%) and apatho-adynamic (18 patients; 56. 2%). Thus, in accordance with the two-level psychopathological model of depression [24], its first 2 types were defined as typical, representing positive affectivity (dreary and anxious depressions), apatho-adynamic depressions as atypical and related to negative affectivity.

According to the sum of scores on the Hamilton Depression Scale (HAM-D) before treatment: mild depressive disorders were registered only in 2 (6.25%) people, moderate - in 13 (40.6%), severe depression was in 17 (53.15%), i.e., the vast majority of patients had moderate to severe depression.

The study used venlafaxine, sold under the name Velaxin in 75 mg tablets by Egis (Hungary). The drug was administered orally, starting with 37.5-75 mg per day. In the future, based on the condition of the patients, over the next days the daily dose was increased, bringing it to the maximum for this patient, but not more than 300 mg. On average, the highest mean dose of Velaxin used was 182.1-198.2 mg per day. The drug was taken twice, in the morning and in the evening. According to the study protocol, Velaxin therapy was 56 days (8 weeks).

To assess the severity of depressive symptoms and determine the therapeutic effect, in addition to the method of clinical observation, the HAM-D-24 scale containing 24 signs was used. The severity of depressive symptoms was assessed before the start of the course of treatment (day 0), then on days 1, 3, 5 of therapy, and then at the end of each of the 8 weeks of course treatment. The effectiveness of the antidepressant action of Velaxin was assessed by the degree of reduction of HAM-D scores in % in relation to the assessment before treatment in the following gradations: reduction of scores to 20% - as "insignificant", by 21-50% - as "moderate", by 51- 80% - as "good" and 81-100% - as a "significant" effect (including "practical recovery"). A decrease in the total score for HAM-D to 6 or less meant a complete "exit" to remission. Maintaining the HAM-D depression severity score at the same level or increasing the total score was regarded as no effect or “worsening” of the condition. To assess the spectrum of the antidepressant action of Velaxin, the degree of reduction in the average total score of individual signs identified in the HAM-D, conditionally characterizing melancholic or melancholy (points 1-3, 22-24), apatho-adynamic (points 7 and 8) and anxious (points 9and 10) manifestations in the structure of a depressive state.

In addition, the severity of the depressive state and the degree of its improvement over time were assessed within the above timeframes using the CGI clinical impression scale and its CGI-S and CGI-I subscales. To register side effects, the UKU interview scale was used, which consists of 4 subscales that make it possible to distinguish mental, neurological, vegetative and so-called other side effects.

Results

During the prescribed 56-day course of treatment with Velaxin, 31 (96.9%) people were recognized as responders, of which "insignificant" effect from the treatment was observed in 1 (3. 1%) patients, "moderate" - in 3 (9, 4%), "good" - in 2 (6.25%), and 25 (78.1%) patients showed a "significant" therapeutic effect. Thus, a decrease in the intensity of depressive disorders by 50% or more during treatment with Velaxin was found in the vast majority of cases - in 27 (84.4%) patients, which is shown in Fig. 1

Rice. 1. The severity of the therapeutic effect of Velaksin in endogenous depression. On the abscissa - the degree of reduction according to HAM-D,%; along the y-axis - % of patients.

In general, the effectiveness of Velaxin, assessed on the 56th day of therapy, was quite high: the average total depression score according to HAM-D was reduced by 85.9%. Already by the end of the 1st week of therapy with Velaxin, a positive therapeutic response to the drug was observed: the reduction in depression was at the level of a “slight” effect, but approached a 20% level of reduction in disorders bordering on a “moderate” improvement. A distinct "moderate" improvement (reduction of the HAM-D score by 33. 2%) was observed by the 14th day of treatment; between the 21st and 28th days of treatment, the therapeutic effect reached the “good” range with a decrease in HAM-D scores by 50% or more, and by the 6th week, the effect of Velaxin treatment was already approaching the “significant” border (up to 76.7% reduction in the severity of symptoms of depression). In the next 7-8 weeks of therapy, an indisputable "significant" improvement in the condition of patients was found (reduction of disorders by more than 80%), up to "recovery" (Fig. 2). In 20 out of 31 patients (in 64.5% of cases) who completed the course of treatment with Velaxin, depression was completely reduced and there was an "exit" to remission (their total HAM-D score became 6 or lower).

Rice. 2. Spectrum of therapeutic action of Velaxin in endogenous depression (HAM-D score). Here and in Figures 3, 4 and 5 (the last one shows the right axis): along the y-axis - the average score in % of the score before the start of therapy, along the abscissa - the day of therapy.

The severity of the condition, assessed by the CGI-S subscale, decreased on average during treatment with Velaxin from 4.7 to 1.6 points by the end of the study (from “significantly pronounced” to less than “mildly expressed”, i.e. to almost no disorders). Moreover, a noticeable decrease in the severity of symptoms was noted between the 7th and 21st days of treatment, when the intensity of depression manifestations consistently decreased on average to "moderately" and "weakly" pronounced. From the 5th week of therapy, the severity of depressive disorders became "very weak", and on the 7th-8th week of the course therapy there was a practical "exit" from depression with the "absence" of depressive symptoms (the average level of their severity was 1.6 points). During the 56-day course of therapy, an assessment of the degree of improvement in the depressive state on the CGI-I subscale showed a “deterioration” in the mental state (5th level of assessment) only in 1 (3.1%) person, remained “unchanged” (4th level). assessment level) also in 1 (3.1%) patient, "slight improvement" (3rd level) - also in 1 (3.1%), "pronounced" improvement (2nd level) was observed in 4 (12 .6%), the remaining 25 (78.1%) patients showed "significant" improvement (grade 1).

It was found that in the spectrum of the antidepressant action of Velaxin, all 3 components of its psychotropic activity, in accordance with the final results of treatment, are represented almost equally with a slight advantage in terms of antidepressant action (see Fig. 2). Thus, the degree of reduction in the average total score of disorders on points 1-3 and 22-24 of HAM-D (reflecting the actual thymoleptic effect of the drug) was 88.2%, on points 7 and 8 (stimulating effect) - 83.7%, and on paragraphs 9and 10 (anti-anxiety action) - 85.1%. However, the implementation of all 3 components of the action of Velaxin was different in time and had its own characteristics. Thus, thymoleptic and especially anxiolytic effects were detected most quickly during treatment. They developed almost in parallel, reaching the level of reduction in the severity of disorders according to HAM-D by 32.8 and 37.1%, respectively, already by the 14th day of therapy (“moderate” effect). At the same time, the stimulating effect of Velaxin was somewhat "late" in comparison with the anti-anxiety and anti-sadness effects, reaching similar values ​​("moderate" effect - reduction of disorders by 36.9%) only by the 21st day of the study.

Later, in the period from the 21st to the 28th days of treatment, the thymoleptic and anti-anxiety components of action in the spectrum of antidepressant activity of Velaxin leveled off in terms of the rate of development and increased to the range of a distinct "good" effect (reduction of the score by 60.2 and 59 .2%). But already from the 5th week of treatment, the thymoleptic effect proper began to surpass the anxiolytic effect in terms of the depth of reduction of disorders according to the corresponding HAM-D items: the thymoleptic effect was manifested at the “significant” level already at the 6th week, and the anti-anxiety effect only after the 7th week course therapy. The formation of the stimulating effect was “delayed” in terms of the degree of manifestations compared with the other two components of the action of Velaxin at week 1, and its “significant” severity was determined only at the 8th week of treatment. And only at this stage of treatment, as already mentioned, the depth of the stimulating effect of Velaxin approximately coincided with the severity of the thymoleptic and anxiolytic effects.

In accordance with the established data on the features of the implementation of individual components of the antidepressant action in the spectrum of psychotropic activity of Velaxin, its therapeutic efficacy was analyzed depending on the syndromic type of depression, i.e. on the dominant affect that determines the picture of the depressive state (Fig. 3). It was found that with the leading anxiety affect, the reduction in the average total score for HAM-D was 85.5% by the 56th day of treatment; with the predominance of apato-adynamic affect, the effectiveness of Velaxin was similar - the average total score for HAM-D decreased by 85. 9%. The highest efficacy of Velaxin was observed in the treatment of patients with the leading melancholy affect in the picture of depression - the reduction in the average total score according to HAM-D was 91.1%. But with a relatively similar degree of reduction in depressive symptoms, differences were also noted in the dynamics of the implementation of the antidepressant effect of the drug. So, with leading anxious and melancholy affects, i.e. in patients with positive affectivity and the most typical manifestations of depression, the reduction of depressive symptoms proceeded at an equal rate, reaching 21.1% (with anxiety) and 22.5% (with melancholy depression) already by the 7th day of therapy. Subsequently, the decrease in the average total score for HAM-D was more intense and reached more than 50% reduction in symptoms of depression by the 28th day of treatment. Treatment with Velaxin in patients with negative affectivity (atypical apatho-adynamic depression) improved more slowly. The reduction of the average total score on HAM-D by 20% or more ("moderate" effect) occurred in them only at the 2nd-3rd week of therapy; and only by the 4th week a “good” effect of Velaxin was recorded (reduction of disorders by 61.3%). By the 7th-8th week of treatment, the improvement in the condition was already “significant” (more than 80% reduction in disorders), it coincided in severity with the therapeutic effect of Velaxin in anxious depressions and somewhat “lagged behind” the effect in melancholy depression.

Rice. Fig. 3. Dynamics of Velaxin efficacy in different types of endogenous depression (HAM-D score).

An analysis of the effectiveness of Velaxin depending on the nosological affiliation of depression also revealed some features (Fig. 4): the smallest decrease in the average total score for HAM-D by the end of the course of treatment was in patients with low-progressive schizophrenia, it was equal to 82.3%. In these same patients, the slowest rate of reduction of depressive disorders was also noted - by the 7th day it was only 15. 2%, and a reduction of 50% or more (the border of the "good" effect) was achieved only by the 28th day; A "significant" effect was found in patients with low-progressive schizophrenia only after the 7th week of Velaxin treatment. In patients with an affective disease (MDP, cyclothymia), the reduction in the mean total HAM-D score at the end of course therapy was close in value (86.6%), and the rate of decrease in depressive symptoms was similar: by the 7th day, this indicator reached 18 .2%, and by the 4th week of therapy it was already 59.4% ("good" effect). The best result of therapy was achieved in patients with postpsychotic depression with paroxysmal schizophrenia - 90.4% reduction of disorders on the 56th day of treatment. Despite the fact that by the end of the 1st week of the study, the rate of reduction of depressive manifestations reached gradations of "insignificant" improvement (19.2%), further reduction in symptoms of depression was more intense than with MDP, demonstrating a "good" effect already by 14 Day 1 of treatment (symptom reduction score -53. 9%), and by the 28th day it was already 76.5%, that is, it was almost on the border of "significant". However, it should be noted that in these patients, the severity of depressive disorders was initially significantly lower, at the level of "moderate" severity, than in other, more "severe" depressions (23 points according to HAM-D versus 31.3 points for affective illness and 31.6 for low-progressive schizophrenia).

Rice. 4. Antidepressant effect of Velaxin in different nosological groups of patients (HAM-D score).

All the indicated patterns of development of the therapeutic effect of Velaxin indicate the absence of a direct dependence on the value of its daily dose. As can be seen from Fig. 5, the therapeutic effect began to appear and increase from the 3rd–4th week of treatment (reduction of depression symptoms by 50% or more according to HAM-D), with an increase in the average daily dose to the maximum (182.1–198.2 mg per day) . But in the future, despite the stabilization and even a slight decrease in the achieved maximum average daily dose of Velaxin (up to 190. 3 mg per day), response to therapy continued to increase at a faster rate, to a level of "significant" improvement,

Rice. 5. The ratio of the therapeutic effect (HAM-D score) and the daily dose of Velaxin. On the left y-axis - the average daily dose of the drug (mg).

During course therapy with Velaxin, 45 adverse events of various types were recorded in 21 (65.6%) patients; in 5 they were single, and in 16 they were combined. The most frequent were mental and vegetative adverse events noted on the UKU scale, they occurred in 40% of patients. 1 patient dropped out of the study ahead of schedule (after 2 weeks of treatment) due to the development of acute affective-delusional psychosis, requiring a change in therapy. Neurological and other side effects occurred in only 8.9and 11.1% of patients. The most common among the individual side effects were such as "agitation/anxiety" (in 15.5% of patients), decreased sleep duration and nausea (in 11.1%), tachycardia and hyperhidrosis (in 6. 6%), sedation and constipation (in 4.4%). All other side effects occurred in isolated cases. The frequency of side effects during course treatment with Velaxin was highest on the 2nd week of treatment, when the average daily dose of the drug was insignificant (157.7 mg per day). The most frequent during this period were mental and autonomous adverse events. But in the future, despite the increase in the average daily dose, the incidence of side effects gradually decreased. The exception was "other" side effects, the frequency of which practically remained at the same level until the end of treatment. These were mainly violations of sexual functions, which developed in accordance with an increase in the daily dose of Velaxin.

It should be noted that, in general, all adverse events were mild or approached moderate in the first 2 weeks of treatment, and then the average degree of their severity, as assessed by UKU, decreased to a “mild” level, despite a gradual increase in the average daily doses of Velaxin. At the same time, mental side effects were initially the most severe: the average UKU score for their severity at the 1st–2nd week of treatment was 1.9–2.0. However, in the course of further course treatment, the severity of adverse mental symptoms decreased from the 3rd week. The severity of some other adverse events slightly increased compared to the initial one: if on the 2nd week of treatment their severity corresponded on average to the UKU of a “mild” degree (1 point), then in the future they reached 1.5 points, and at the same time their degree severity increased correspondingly with an increase in the mean dose of Velaxin.

Discussion

The results of the clinical use of Velaxin in endogenous depression showed its high antidepressant activity. In 84.4% of patients, there was a clear positive therapeutic effect with a decrease in the severity of disorders (according to HAM-D) by 50% or more. Of these, the majority (78.1%) achieved a "significant" therapeutic effect with a reduction in the HAM-D score by more than 80%, and in 62. 5% of patients, at the end of the 8-week course treatment with Velaxin, a good quality remission occurred with complete "out" of depression. The distinct antidepressant properties of Velaxin are also evidenced by the inversion of depressive affect into hypomanic affect in 2 patients by the end of the course of treatment. It is very important that the therapeutic effect of Velaxin manifests itself early, already at the 2nd week of treatment it is determined at the level of "moderate" (up to 50% reduction in the severity of symptoms according to HAM-D), and by the 3rd-4th week of therapy, the reduction of the HAM score -D reached 50% or more ("good" effect).

According to the clinical characteristics, Velaxin can be legitimately classified as a balanced antidepressant. In the spectrum of its antidepressant activity, all 3 components of the antidepressant effect are approximately equally represented with a certain predominance (in terms of depth of effect) of the thymoleptic effect, an earlier anxiolytic effect and a “lag” in the timing of the manifestation of the stimulating effect. These properties of the antidepressant activity of Velaxin ensured its high therapeutic efficacy in the treatment of syndromic different types of depressive states - anxiety, apatho-adynamic and, primarily, melancholic. By the end of the course of treatment, the effectiveness of Velaxin in anxiety and apatho-adynamic depression "stopped" at the level of 85.5 and 85.9, respectively.% reduction of disorders according to HAM-D, and with melancholy depressions was deeper at this stage of treatment and reached 91.1% reduction of the corresponding symptoms.

Features of the spectrum of therapeutic action of Velaxin depend on the nosological affiliation of the disease and the form of its course. In cases where the basis of the clinical essence of an endogenous disease was a distinct property of phase- or paroxysmal formation (MDP, cyclothymia, paroxysmal schizophrenia), the effectiveness of Velaxin in the treatment of depression was higher than in cases of diseases in which depression developed as part of exacerbation against the background of continuous (sluggish) ) course (low-progressive schizophrenia). But in general, the depth of therapeutic improvement in all these diseases was quite high, respectively, at the level of 86.6; 90.4% and 82.3% reduction in HAM-D depressive symptom severity score.

The results of the study substantiate the expediency of prescribing long-term courses of treatment with Velaxin, since the formation of its therapeutic effect at the level of "good" begins only from the 3rd-4th week of the course of therapy, and the "significant" effect is achieved only at the 2nd month of treatment. The data obtained allow us to recommend moderate daily doses of the drug to achieve a "significant" therapeutic effect and "exit" into remission: doses of 180-19 can be considered optimal.8 mg, i.e. 2-3 tablets per day (75 mg each), since a further increase in the daily dose does not lead to a clear increase in the clinical effect.

In general, Velaxin is well tolerated, rare side effects associated with its administration are mild or moderate and develop mainly in the first 2 weeks of treatment; they do not require discontinuation of the drug and do not affect the regimen of therapy. Despite ongoing treatment and an increase in daily doses of Velaxin, the severity and frequency of adverse events are decreasing, which may justify their dose-independence. It is important to note that such severe side effects as urinary retention, lowering blood pressure, dry mouth, vomiting, convulsions, orthostatism, which are usually characteristic of tricyclic antidepressants, did not occur during treatment with Velaxin.

Possessing a wide range and depth of antidepressant action, as well as good tolerance, Velaxin can be recommended as a drug of choice in the treatment of nosologically various endogenous diseases that occur with a picture of depression, both moderate and severe. Velaxin, a drug with a distinct antidepressant activity of balanced action, at the present stage of the development of psychopharmacotherapy can rightly be classified as an active antidepressant as a highly effective representative of the third generation of this class of psychotropic compounds.

Clinical efficacy and tolerability of venlafaxine (Velaxin) in the treatment of moderate and severe depression :: DIFFICULT PATIENT

S.N. Mosolov, E.G. Kostyukova, A.V. Gorodnichev, I.V. Timofeev, M.Ya. Ladyzhensky, O.V. Serditov

Moscow Research Institute of Psychiatry, Roszdrav

The treatment of depressive spectrum disorders, from the 1960s to the present, remains a complex and urgent problem. Despite the variety of antidepressants available in the arsenal of psychiatrists, there is a large group of patients in whom known drugs are ineffective or cause undesirable effects. In this regard, studies of the pathogenesis of depression and the mechanisms of action of antidepressants are actively continuing, which makes it possible to synthesize new effective drugs with an improved tolerability profile and a more powerful mechanism of action.
Venlafaxine is the first third-generation thymoanaleptic (selective serotonin and norepinephrine reuptake inhibitor - SNRI), followed by a whole group of such drugs (milnacipran, duloxetine). It should be noted that venlafaxine is the most studied and most commonly prescribed drug from the SNRI group and is used in many studies (in order to prove the effectiveness of new antidepressants) as a reference.
In the last decade, convincing data have accumulated on the high effectiveness of tricyclic antidepressants (TCA) compared with SSRIs in the treatment of severe, including melancholic depression. The results of two independent studies are known [1, 2], which compared the effectiveness of clomipramine, citalopram and paroxetine. The therapeutic response in treatment with clomipramine was 2 times higher than that of citalopram (60 and 30%). Similar results were noted when comparing clomipramine and paroxetine. The superiority of TCAs in the treatment of severe depressive states was also revealed in two meta-analyses conducted by Anderson [3, 4]. They confirmed that TCAs with a broad, non-selective mechanism of action (amitriptyline and clomipramine) are more effective than SSRIs. In our country, similar data were obtained by A.B. Smulevich and S.N. Mosolov on the material of open studies [5, 6].
The results of these studies, as well as clinical practice, led to the idea to enhance the effectiveness of antidepressants by expanding the neurochemical application, which became the basis for the synthesis of a new generation of antidepressants, namely: a wide range of clinical action; 2) compared to TCAs, dual action antidepressants are safer; 3) "dual" action antidepressants have a number of features and specific effects. These provisions, as shown by clinical practice, were fully realized in the process of using the "double" action antidepressant venlafaxine.
Venlafaxine, having a wide therapeutic range of doses, consistently includes serotonergic, noradrenergic and dopaminergic effects in the spectrum of its neurochemical activity. So, at a dose of 75-125 mg, venlafaxine exhibits a serotonergic effect, when the dose is increased to 225 mg, the noradrenergic effect is turned on, and a further increase in the dose to 375 mg leads to the appearance of a dopaminergic effect. Such a dose-dependent pharmacology of venlafaxine fundamentally distinguishes this drug from SSRIs, a limited range of therapeutic doses, which narrows the possibility of other neurochemical effects other than serotonergic ones [7].
The high efficacy of venlafaxine has been demonstrated in comparative studies with TCAs. Thus, a comparison of venlafaxine and clomipramine did not reveal differences in the antidepressant effect, with slightly better tolerability of venlafaxine due to a lower frequency of anticholinergic adverse events (p ≤ 0.05) [8]. Venlafaxine is as effective as amitriptyline [9] and imipramine, although the doses used in the study were close to the maximum (imipramine 179 mg/day versus venlafaxine 183 mg/day) [10].
A meta-analysis of 19 studies including 2181 patients showed that the side effects of venlafaxine, the frequency of which exceeds 10%, include: nausea, headache, insomnia, drowsiness, dry mouth, dizziness, constipation, asthenia, sweating and nervousness [ eleven]. Of these, nausea is the most common adverse event and leads to drug withdrawal in 6% of cases. At the same time, the frequency of occurrence of this undesirable effect decreases by 50% already after the 1st week of therapy and further - during the entire course of treatment. Anticholinergic side effects occur with venlafaxine 2 times less frequently than with TCAs.
However, some side effects of venlafaxine are noted to be dose-dependent (which is a direct reflection of the drug's dose-dependent pharmacology). These include with high certainty such serotonergic adverse events as nausea, insomnia and sexual dysfunctions [12].
The aim of this work was to study the efficacy, features of thymoanaleptic action and tolerability of the drug venlafaxine in the treatment of moderate and severe depression.
The study was open, non-comparative. The duration of the study was 6 weeks.
The study included patients aged 18 to 65 years with an ICD-10 diagnosis of recurrent depressive disorder (F32. 1), moderate or severe depressive episode (F33.1 or F33.2), bipolar affective disorder (F31): episode moderate or severe depression (F31.3 and F31.4). The minimum sum of points when assessed on the 17-point Hamilton Scale (HH) was at least 17, and on the Global Clinical Impression Scale (GCI) - at least 4 points. The study included patients who gave written informed consent to participate in it. Quality of life was also assessed using the WHO Brief Quality of Life Scale at baseline and end of the study.
The exclusion criteria were the period of pregnancy and lactation in women; high suicidal risk for outpatients; any clinically significant uncompensated diseases of the kidneys, liver, cardiovascular, respiratory system, cerebrovascular disorders or other serious progressive somatic diseases; organic diseases of the central nervous system, any of the listed methods of treatment at the indicated time intervals before the start of the study: MAO inhibitors (including reversible ones) - 2 weeks; electroconvulsive therapy - 3 months; depot forms of neuroleptics - 4 weeks.
Patients who were taking any psychotropic medication prior to study entry were subject to a 7-day "wash out" period.
In the first two weeks of the study, including the "withdrawal" period, hypnotics were allowed to correct sleep disorders and anxiolytics (with the exception of alprazolam) for anxiety symptoms that could lead to premature termination of the study. Subsequently, this concomitant therapy was discontinued in all patients, with the exception of those who took benzodiazepine tranquilizers for a long time before the start of the study. No specific psychotherapy was used in the study. Patients were given explanations about their condition, including the expected effect of the drug.
During follow-up, the severity of depressive symptoms was recorded using the Hamilton Scale for Depression (17 items) (HAM-D), the Global Clinical Impression (CGI) Scale and the WHO Concise Quality of Life Scale. The condition of patients was assessed immediately before the start of the drug (day 0 of therapy), and then on days 4, 7, 14, 21, 28, 35, and 42 of treatment. On the same days, throughout the study, all emerging adverse events (AEs) were recorded with an indication of their severity, time of occurrence and duration. An AE was any adverse (medically) event that occurred in a patient receiving study drug, or regardless of its causal relationship to it. Worsening of the patient's pre-study symptoms was also recorded as an adverse event.
The study included 30 patients, of which 26 (86.6%) women and 4 (13.4% men). The mean age of the patients was 43.6 ± 2.7 years.
The duration of the disease averaged 13.0 ± 1.9 years, the number of previous depressive episodes was 6.6 ± 1.2. The duration of the present episode of depression averaged 3.6 ± 1.22 months. Drug treatment of the current depressive episode before the start of the study was carried out in 13 (50%) patients.
Baseline mean group score for the first 17 HAM-D items was 21.96 ± 2.4. According to CGI, the average disease severity score for the group was 4.34 ± 0.48 points.
Venlafaxine (Velaxin) was given as a single daily dose of 75 mg/day followed by an increase to 150 mg/day in 2 divided doses during the first week. With insufficient effectiveness of the drug, the dose was increased to 225 mg / day. The dose increase was carried out 3 weeks after the start of therapy. The mean daily dose of venlafaxine was 137.5 mg/day.
Completed the study 26 patients. One patient withdrew due to refusal to continue the study, 2 patients withdrew due to deterioration between days 14 and 21 of therapy, and 1 patient withdrew due to adverse events on day 3 of therapy.

Results of the study
When analyzing the data, the following results were obtained. The overall effectiveness of therapy by the end of the study for SH (the percentage of patients with a reduction in the total score by at least 50%) was 77% (20 out of 26 patients). Qualitative remission (≤ 7 points) by the end of the study was established in 61%. According to the CGI scale, a positive effect (pronounced and significant improvement) was observed in 18 (69%) patients.
Already at the second week of therapy, 40% of patients were assessed as responders to ongoing therapy, by the third week of therapy 50% were responders, and by the 6th week of treatment their number exceeded two thirds of the total number (20 out of 27-74. 7%) . A significant increase in the number of responders by the 3rd week of therapy indicates a fairly rapid effect, somewhat ahead of the time characteristic of most antidepressants. From fig. Table 1 shows that the increase in the number of patients with a positive effect of therapy was observed until the end of the study, although it was most pronounced between the 3rd and 5th weeks of therapy, which suggests a fairly rapid onset of the effect in comparison with other new generation antidepressants, as well as Extend recommendations to continue therapy for at least 6 weeks for venlafaxine.
These data are also confirmed by the analysis of the dynamics of depression severity indicators according to CGI. A change in the severity of the disease was observed already on the 7th day of therapy (p The effect of therapy occurred quite quickly. The value of the total SH score for the group as a whole decreased by 12% already on the 4th day and by 23% on the 7th day of treatment ( the changes are statistically significant, p ≤ 0. 01) (Fig. 2). Subsequently, there was a consistent decrease in the severity of depressive symptoms. By the end of the study, the total score of SH was 6.9± 0.9 points, which practically corresponds to the generally accepted indicator of therapeutic remission for SH and indicates a distinct antidepressant effect of the study drug.
The main indicators that determine the spectrum of the psychotropic action of the antidepressant (low mood, mental anxiety and lethargy) decreased fairly evenly (Fig. 3), the statistical significance of changes for each indicator was observed already on the 7th day of therapy (p Despite a fairly harmonious reduction in anxiety and lethargy, in the first days the reduction of anxiety symptoms prevailed, but by the end of the first week of therapy, the reduction in indicators leveled off.0096 The nature of the thymoanaleptic effect is clearly confirmed by the analysis of the coefficient (K) of the ratio of anxiety reduction and lethargy (Fig. 4). The value of K, equal to 1, reflects a uniform reduction in the SH indicators "mental anxiety" and "lethargy" and indicates a balanced thymoanaleptic effect of the drug. As can be seen from fig. 4, at the beginning of therapy, the K value was significantly greater than 1, especially from the 4th day until the 21st day of therapy. This means that at the beginning of therapy, anxiety was reduced much faster than inhibition. In the study, this led to a rapid reduction in anxiety symptoms, the absence of the need for additional use of tranquilizers. However, by the 4th week of therapy, the effect of venlafaxine becomes balanced until the end of the course of therapy.
It has already been mentioned above that venlafaxine, used in different doses, can have different effects on the reduction of depressive symptoms. Thus, venlafaxine at a dose of 75-150 mg / day affects mainly serotonergic transmission and is similar to SSRIs. The reduction in the anxiety/lethargy ratio for the group of patients who took venlafaxine at doses up to 150 mg/day is shown in Figure 5.
influence on lethargy, however, by the end of the first week, the action of venlafaxine became more balanced with an extremely insignificant activating effect after a month of therapy.
The effect of venlafaxine at a dose of more than 150 mg/day on the coefficient of reduction of anxiety/lethargy is somewhat different (Fig. 6).
Noteworthy is the long-term, up to the 3rd week of therapy, the predominance of the reduction of anxiety symptoms in relation to the reduction of lethargy, which was assessed by patients as the absence of anxiety and did not require anxiolytics. Subsequently, until the end of the study, the drug prescribed at this dose was characterized as a balanced antidepressant with a mild sedative effect.
Clinically, at the end of the first week of treatment, most patients felt better. Along with a rapid decrease in the severity of anxiety, there was an improvement in sleep. Patients noted an improvement in the quality of sleep, it became deeper, a feeling of cheerfulness returned when waking up in the morning. The results are shown in Figure 7.
A rapid decrease in the severity of anxiety allowed most patients to stop taking anxiolytics prescribed during the "wash out" period or at previous stages of treatment. Objectively, patients became more contact, more active in conversation, noted that the interest lost during the period of depression in the usual range of activities and hobbies was beginning to be restored. These changes were reflected in the analysis of the WHO Brief Quality of Life Scale (Fig. 8).
The results show a high reliability of improvement in this indicator (p ≤ 0.01) in patients after the course of therapy compared with the moment of inclusion in the study.
In the present study, venlafaxine appeared to be well tolerated. In one case, a patient was withdrawn from the study due to mydriasis. The adverse event was not severe, but the patient refused to continue therapy and dose adjustments. In 14 (43.3%) of 29 patients, 20 cases of AE were registered, however, the relationship of their development with venlafaxine was assessed as "probable" only in 6 cases, and in other cases as "supposed". Assessment of the intensity of AE showed that 12 (60%) of 20 cases of AE were of low intensity, 8 (40%) were moderate. In most cases, no measures were taken regarding therapy, but in 5 of 20 (40%) cases, the dose of the drug was reduced. All AEs that occurred during the study period and occurred with a frequency of more than 1 case are presented in the table.
As can be seen from the table, nausea and mydriasis occupy the largest share among AEs. In most cases, they appeared in the first two weeks of therapy. Drowsiness, as a rule, was observed on the 1st week of treatment, which, along with indicators of the dynamics of the ratio of anxiety reduction and lethargy, probably reflects some sedative effect of the drug in the first days of therapy. Analysis of the outcomes of AEs showed that in the vast majority of cases (80%) AEs were transient. In most cases, they developed in the first week of therapy when using a dose of 150 mg / day and, in the future, as therapy continued, they were reduced. With a further increase in the dose of the drug in most patients, an increase in the frequency of AE, as a rule, did not occur. In addition, after the first week of therapy, adverse events were noted only when using doses of 150 mg / day.

Discussion
Summing up the results of the study, it is necessary to note the high efficacy of venlafaxine, and, most importantly, a 50% reduction in symptoms occurred fairly quickly, on the 2-3rd week of therapy. There are data in the literature on an earlier clinical response (within the 1st, rarely 2nd week of therapy) when using high doses of venlafaxine [13, 14, 15]. However, the design of these studies was based on the rapid buildup of venlafaxine. The most revealing study compared 3 groups of patients taking different doses of venlafaxine (75 mg - the first group; 150-225 mg - the second group; 300-375 mg - the third group). The results of this work showed that in the 1st and 2nd groups of patients, the onset of the primary response was observed in the first 2 weeks of therapy, while in the 3rd group of patients taking the highest dose of the drug, a statistically significant effect was noted already in the 1st week of treatment [15]. The dose escalation regimen in the present study differed from those described above in greater flexibility, which allowed the safe and effective use of venlafaxine for the treatment of depressive disorders in outpatients. It is clear that a rapid dose escalation strategy that allows full use of the dose-dependent effect of venlafaxine is especially appropriate in the treatment of major depressive disorders in an inpatient setting.
The dose-dependent effect of venlafaxine, associated with the gradual inclusion of various mediator structures (serotonin, norepinephrine, dopamine) into the orbit of the drug's influence, indirectly leads to a difference in the features of the clinical action. Thus, in the study, the drug used in high doses (more than 150 mg/day) proved to be predominantly sedative, while in smaller doses it had a more balanced effect.
The drug was quite well tolerated. None of the patients had severe adverse events, the vast majority of side effects were dose-dependent and were observed mainly in the first 2 weeks of therapy.
Given the rather pronounced sedative effect of the drug in the first weeks of therapy and the ability to control it depending on the dynamics of the dose, as well as the rapid reduction of sleep disturbances and the balanced nature of the action after 3 weeks of therapy, it can be noted that venlafaxine is one of the optimal drugs of choice for depressive patients on an outpatient basis.
Thus, summarizing the results of the study, we can conclude that venlafaxine has a distinct thymoanaleptic effect and has a balanced effect on the symptoms of anxiety and lethargy, with a moderate sedative effect in the first week of therapy. Of particular importance is the ability of the drug to quickly reduce depressive disorders of any severity, as well as a wide range of comorbid depression and anxiety disorders.

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