Depression: medications (antidepressants)

Pharmacological treatment of depression

The efficacy of antidepressants in major depression has been demonstrated in numerous placebo-controlled studies that collectively encompassed tens of thousands of patients. On average, antidepressants are effective in 55-65% of patients. Over the past decade, the arsenal of funds for the treatment of depression has expanded significantly. Significant progress has been made in the development of new products with higher safety and tolerability.

Read also: 8 things you need to know about antidepressants

At the beginning of the 20th century, the main method of treating major depression was "shock" therapy, which was carried out by the administration of insulin, which caused hypoglycemia, or horse serum. In the 1930s, ECT was used, which was a great achievement in this field. ECT is now considered to be a very effective and safe method of treating major depression. Along with other methods, this method is used in severe depression, depression with psychotic symptoms, mixed episodes of bipolar disorder, as well as in the event of an immediate threat to life due to suicidal intent or refusal to take food and drink.

In the 1940s and 1950s, psychostimulants (for example, D-amphetamine and methylphenidate) were used as antidepressants, but their use was limited due to side effects. Psychostimulants are still used as adjuvant (to enhance the effect of antidepressants), and sometimes as a monotherapy in elderly or somatically weakened patients, although the effectiveness of this method in controlled studies has not been proven. In the mid-1950s, there was a significant breakthrough in the pharmacotherapy of major depression, when it was inadvertently discovered that iproniazide, an inhibitor of monoamine oxidase (MAOI) used to treat tuberculosis, can boost mood. The same properties were found in imipramine, which was developed as an alternative to neuroleptic chlorpromazine. However, it turned out that the drug does not have antipsychotic properties, but it can be used as an antidepressant. For the treatment of depression, imipramine began to be used in the US in 19S8. In the next few years, a whole series of new antimicrobial antidepressants (TCAs) appeared that had a similar pharmacological and clinical effect. TCAs belonging to secondary amines (for example, desipramine, which is a metabolite of imipramine, or nortriptyline-metabolite amitriptyline), were safer than tertiary amines, but still could cause a number of serious side effects. In 1982, trazodone was introduced into clinical practice, which was widely used until the first drug from the group of selective serotonin reuptake inhibitors - fluoxetine (Prozac) appeared in 1988. Fluoxetine was the first drug from the SSRI group approved by the FDA to treat depression. However, five years earlier in Switzerland, another drug from the SSRI group - fluvoxamine (luvox) began to be used. SSRIs revolutionized the treatment of major depression, as they caused significantly fewer side effects and were more convenient to use without requiring as long a titration dose as TCA and MAOI.

The importance of SSRIs has evolved into a purely medical framework, they have become an integral part of American culture and have spawned a number of issues related to their use. Thanks to these drugs, public opinion has improved the understanding that severe mental illnesses have biological roots, and psychiatric diagnosis and the need for psychiatric treatment by many have ceased to be perceived as a stigma. At the same time, there were questions - are not too often prescribed antidepressants and does pharmacotherapy prevent other effective methods of treatment of mental disorders?

In 1993, four years later than fluoxetine, sertraline (zoloft), followed by paroxetine (paxil), were approved by the FDA and began to be used in the treatment of major depression. Later, the FDA approved the use of these two drugs for panic disorder and obsessive-compulsive disorder (OCD). Fluvoxamine was approved for use in the US only for the treatment of OCD, but in many countries it is also used to treat depression. A little later, another representative of the SSRI group, citalopram (cipramil), was widely spread.

Recently, the clinical practice has been introduced so-called atypical antidepressants, differing in the mechanism of action from SSRIs. Bupropion (wellbutrin) - monocyclic aminoketone - first appeared on the pharmaceutical market in 1989. Nevertheless, the mechanism of its operation remains unclear until now. Venlafaxine (effector) - a double inhibitor of reuptake (both serotonin and norepinephrine) - is close to the mechanism of action to TCAs, but, unlike them, is devoid of a number of serious side effects, including no toxic effect on the heart. Nefazodone (serzone), a drug that is pharmacologically related to trazodone, is a weak inhibitor of reuptake of serotonin and norepinephrine and a potent 5-HT 2 receptor antagonist. The last recently approved antidepressant is mirtazapine (re-meron), an antagonist of 5-HT2 and 5-HT3 receptors and an α2-adrenoreceptor alpha agonist. Many countries (but not in the US) use reversible monoamine oxidase inhibitors, such as moclobemide, which, unlike traditional irreversible MAO inhibitors, do not require dietary restrictions.

Choosing an antidepressant

In slightly more than half of cases after the first episode of major depression, the disease recurs, but it is impossible to predict its further course in the debut of depression.

When choosing a drug that can be prescribed for many years, it is necessary to take into account its effectiveness, side effects, possible interactions with other drugs, the cost of the drug and the mechanism of its action. The goal of treatment is to restore the state of complete euthymy, and not just to mitigate the symptoms, which can only be regarded as a partial therapeutic effect. The effect of monotherapy with the first drug chosen may not be sufficient to meet the long-term goal, but before proceeding with combination therapy, one should try to find a drug whose monotherapy would have the desired effect.

Possible side effects of antidepressants are a constant source of anxiety, both for the patient and for the doctor. Many of them can be predicted, knowing the features of drug interaction with different types of receptors.

However, sometimes side effects are of positive significance. For example, in a patient suffering from major depression and comorbid irritable bowel syndrome, the ability of an antidepressant to block M-cholinergic receptors will have a beneficial effect, but in an elderly patient, the anticholinergic action of the drug will exacerbate cognitive impairment. Orthostatic hypotension is more dangerous for elderly women with osteoporosis (since they can break the thigh if they fall) than for younger patients. One of the main problems associated with long-term admission of TCAs is the possibility of an increase in body weight, which is sometimes significant. In patients with difficulty falling asleep, it is often tempting to use an antidepressant with a powerful sedative effect, but it must be remembered that this is only one of the manifestations of depression, and therefore one should treat the disease as a whole, and not its individual symptoms. So, a patient suffering from insomnia, in the beginning, such treatment can help, but then, as the depression worsens, there will be problems associated with a difficult morning awakening.

Between antidepressants and drugs from other groups, drug interaction is possible. This usually occurs through the inhibition of cytochrome P450 enzymes that metabolically degrade other drugs, and by displacing another drug from binding to proteins. The issues of drug interaction are discussed in more detail below.

The cost of treatment is relevant not only for patients, but also for doctors and the health care system. Non-proprietary TCAs (generics) are much cheaper (per pill) than antidepressants of the new generation. However, it should be taken into account that the cost of the drug is only 4-6% of the cost of treatment on an outpatient basis, and the use of more modern drugs that are safer and provide a higher adherence to patient treatment (compliance) ultimately leads to a reduction in treatment costs.

There are several stages of treatment of major depression. According to Kupfer (1991) distinguish between acute, prolonged and supportive stages of treatment. Acute stage - the beginning of treatment in the symptomatic phase of the disease. It involves the diagnosis, prescription of drugs and titration of their dose. The duration of this stage is usually calculated in weeks. As soon as a significant improvement or remission has been achieved, a prolonged stage takes place, which lasts 4-9 months. The episode of depression that developed in this stage is considered a relapse and is usually regarded as a continuation of the same episode, about which the treatment of the acute stage was started. By the end of this stage the patient is in a state of remission after this completed depressive episode. Supportive therapy is given to patients who need to continue treatment. Its duration is not limited, the goal is to prevent the development of a new episode. Supportive therapy is indicated in the recurring course of major depression, especially in those cases when the patient has already suffered three or more depressive episodes of any severity or at least two severe episodes. If at the stage of maintenance therapy there is an increase in symptoms, then it is seen as a new episode of depression, rather than a relapse of the old.

Nomenclature of antidepressants. Groups of antidepressants are called by their mechanism of action (for example, MAO inhibitors or SSRIs) or chemical structure (eg, TCAs or heterocyclic antidepressants). The effect of most antidepressants is associated with exposure to noradrenergic, serotonergic or dopaminergic systems. Antidepressants differ in the intensity of inhibition of re-uptake of different monoamines.

The ratio of the effect of antidepressants on the reuptake of serotonin (5-HT) and norepinephrine (NA), expressed in a logarithmic form (according to data obtained in vitro). The longer the column, the more selectively the drug affects the capture of serotonin; the shorter the column, the more selectively the drug affects the norepinephrine reuptake.

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Tricyclic antidepressants

Over the last thirty years, the effectiveness of tricyclic antidepressants has been repeatedly confirmed in placebo-controlled trials. Before the emergence of antidepressants of a new generation, tricyclic antidepressants were the drugs of choice, and drugs such as imipramine or amitriptyline are still considered in many studies as the "gold standard" of treatment. It is suggested that the main mechanism of action of tricyclic antidepressants is inhibition in the brain of the reuptake of norepinephrine with presynaptic endings, although the drugs of this group inhibit the reuptake of serotonin. The exception is clomipramine (anaphranil), which is a more potent and selective serotonin reuptake inhibitor than other tricyclic antidepressants. Clomipramine is used in the US mainly to treat obsessive-compulsive disorder, but in European countries for many years it is also used as an antidepressant. Tricyclic antidepressants, related to secondary amines, more selectively inhibit the re-uptake of norepinephrine than their tertiary precursors. It is suggested that inhibition of norepinephrine reuptake is the cause of increased behavior and hypertension in some patients taking tricyclic antidepressants.

Tricyclic antidepressants - the only class of antidepressants, which is characterized by a relationship between the level of the drug in the serum and antidepressant activity. The therapeutic concentration of imipramine in plasma is more than 200 ng / ml (including imipramine and desipramine). In contrast, in nortriptyline, the therapeutic window is in the range of 50-150 ng / ml; if the concentration is higher or lower than these values, then its antidepressant effect is weakened.

The side effects of tricyclic antidepressants may limit their use in some patients. Some of them can be weakened if we start treatment with a small dose, and then gradually increase it. Against the background of long-term use of the drug, sedation usually passes, while orthostatic hypotension usually does not decrease with time. A sharp abolition of TCAs should be avoided because of the danger of the ricochet effect caused by the cessation of cholinolytic action and manifested by insomnia and diarrhea. A more serious problem is that, in comparison with many antidepressants of the new generation, tricyclic antidepressants have a low therapeutic index and have an adverse effect on the heart. An overdose with a one-time intake of a 7-10-day dose of the drug may lead to a fatal outcome. Cardiotoxicity in case of overdose is caused by blockade of fast sodium channels, which is typical for antiarrhythmic agents of type 1a.

Treatment usually begins with 25-50 mg / day of amitriptyline, desipramine or imipramine or with 10-25 mg / day of nortriptyline. In the presence of comorbid panic disorder, the lower limit of the indicated dose range should be adhered to, since such patients are very sensitive to side effects. The dose is gradually increased within 7-14 days to the lower therapeutic dose. After 2-3 weeks, a further increase in the dose is possible. In children and people over 40 years before the appointment of tricyclic antidepressants, an ECG is necessary. However, many clinicians conduct an ECG for all patients who are supposed to prescribe tricyclic antidepressants.

A considerable amount of information has been accumulated concerning the approaches to TCA dosing with maintenance therapy and their effectiveness in recurrent depression. Contrary to the practice of using relatively high doses in the acute stage of treatment and lower doses at the stage of maintenance therapy, studies with TCAs show that the dose that is effective in the acute stage should be subsequently maintained with continued and maintenance therapy. The effectiveness of long-term therapy of TCAs with recurrent depression is shown. In one study, patients were selected, the average number of major depressive episodes in which was 4.2, with two episodes occurring in the last 4 years. All subjects were prescribed therapeutic doses of imipramine. Patients with a good response to treatment were randomized. In 80% of patients who continued to take imipramine at the initial therapeutic dose after randomization, there were no exacerbations within 3 years. In the same group where, after randomization, patients took a placebo, 90% of them developed relapses or new depressive episodes.

Although amoxapine and maprotiline are related to tetracyclic antidepressants, they are largely similar to TCAs. Maprotiline is an inhibitor of norepinephrine reuptake. Amoxapine is metabolized with the formation of neuroleptic loxapine, so it can simultaneously affect both affective and psychotic disorders. But since it is a kind of combination of antidepressant and antipsychotic with a fixed ratio of their activity, it is usually not a means of choice, since it is impossible to individually select the dose of a metabolite that has antipsychotic activity. In addition, with prolonged treatment with amoxapine, there is a risk of developing tardive dyskinesia.

Clomipramine is a tricyclic antidepressant with a unique pharmacological effect. Unlike other tricyclic antidepressants, clomipramine more selectively inhibits the reuptake of serotonin (approximately 5 times stronger than norepinephrine). Many consider it a "mixed inhibitor of re-uptake," which has some advantages in treating the most severe cases of depression. However, not all share this view. The scientific group on the study of antidepressants from the University of Denmark in two different studies compared the effectiveness of clomipramine with the efficacy of paroxetine or citalopram. According to the results of these studies, clomipramine, a mixed reuptake inhibitor, surpassed both SSRIs in effectiveness. In another study, comparing the efficacy of imipramine and paroxetine, there were no significant differences, although perhaps the average dose of imipramine (150 mg / day) was too low. Comparison of the efficacy of fluoxetine and imipramine in hospital conditions revealed no differences.

Tricyclic antidepressants have some advantages over new generation antidepressants, including such as convincingly proven efficacy, more than 35 years of experience, a lower cost per tablet, the ability to take the drug once a day. However, they significantly lose due to side effects and relatively low security. Tricyclic antidepressants continue to play an important role in the treatment of major depression, although they are no longer the first choice drugs.

Monoamine Oxidase Inhibitors

In the United States at present, mainly irreversible non-selective MAO inhibitors are used that block simultaneously MAO-A and MAO-B. In other countries, reversible and more selective drugs, such as moclobemide, are used. Due to the fact that these drugs selectively act only on one isoform of the enzyme, their intake does not require dietary restrictions, necessary when using earlier preparations of this group. In the US pharmaceutical market, MAO inhibitors are currently represented by three drugs: phenelzine (nardyl), tranylcypromine (parnate) and isocarboxazide (marplane). They all inhibit MAO-A, the metabolizing norepinephrine, serotonin and adrenaline, and MAO-B, metabolizing phenylethylamine, phenylethanolamine, tyramine and benzylamine. Dopamine is a substrate for both isoforms of the enzyme, but in the central nervous system it is metabolized predominantly by MAO-B.

The therapeutic effect of MAO inhibitors is proportional to their ability to inhibit the activity of MAO platelets. The therapeutic dose of phenelzine is usually 45-90 mg / sug, tranznipromina - 10-30 mg / sug, isocarboxazid - 30-50 mg / sug. Treatment with phenelzin often begins with a dose of 15 mg / sug for 2-4 days, and then it is increased to 30 mg / sug and then every week another 15 mg is added. Treatment with tranylcipromine usually begins with a dose of 10 mg / sug for 2-4 days, after which it is increased to 20 mg / day, and after 7 days, an additional dose increase is possible. The initial dose of isocarboxazide, as a rule, is 10 mg / day, then it is increased to 30-50 mg / day.

Side effects of MAO inhibitors include orthostatic hypotension, drowsiness, insomnia, swelling, tachycardia, palpitations, sexual dysfunction, weight gain. Weight gain and swelling are more pronounced when using phenelzine, an MAO inhibitor from the hydrazine group, than when tranylcip romin is taken. For correction of orthostatic hypotension, it is recommended to increase the intake of water and salt, wear elastic stockings, prescribe fludrohydrocortisone (florinef) or small doses of caffeine.

Due to the danger of unwanted interaction with tyramine-containing products and some cold remedies, MAO inhibitors are not the drugs of choice in depression. When treating with MAO inhibitors, one should avoid eating a meal rich in tyramine. Therefore, products that are long maintained and fermented (for example, many cheeses, smoked foods, marinades, yeast, many varieties of wines and beer) are contraindicated, most drugs taken for colds, dextramethorphan, meperidine and adrenaline, often used together with local anesthetics. Some patients manage to break the diet without serious consequences, but they should be reminded that the content of tyramine even in one piece of cheese can vary greatly, and the possible consequences include an increased risk of stroke and myocardial infarction. Many clinicians prescribe to patients nifedipine (10 mg) or chlorpromazine (100 mg), which the patient must take when a severe headache occurs, and immediately seek medical help.

MAO inhibitors are effective antidepressants. Their effectiveness is proven in case of major depression, depression with atypical symptoms, depression in the bipolar disorder, and also with two anxiety disorders - panic disorder and social phobia.

Trazodone. Trazodone refers to triazolopyridines and differs from other antidepressants in chemical properties and mechanism of action. Unlike TCAs, trazodone has almost no cholinolytic and antiarrhythmic properties, which makes it attractive for the treatment of depression. To treat depression, doses of 400-600 mg / day are usually required, but when taking this dose, many patients experience pronounced orthostatic hypotension and sedation, which limits the use of the drug. Treatment usually begins with a dose of 50-150 mg / day, then it is increased to 400-600 mg / day (daily dose is divided into several doses).

A rare but serious side effect is priapism, which develops on average in 1 out of 6000 men. With any manifestation of erectile dysfunction, for example, with excessive lengthening of the erection or the appearance of it in an inappropriate situation, the patient should be immediately examined. Currently, given its sedative properties, trazodone is often used in combination with SSRIs with persistent insomnia. To do this, usually prescribed 25-100 mg of trazodone for 30-60 minutes before going to sleep.

Bupropion. Bupropion - a compound from the group of aminoketones, is a weak inhibitor of the re-uptake of dopamine and norepinephrine, but does not affect the reuptake of serotonin. It is usually taken three times a day, when using the newly emergent form with delayed release - twice a day. Unlike other antidepressants, in particular SSRIs, bupropion does not affect sexual function, which is its big advantage. In addition, bupropion does not have anticholinergic action, and an increase in body weight against the background of its administration is very rare. There is evidence that bupropion less often provokes a transition from depression to mania in patients with bipolar disorder.

The entry of bupropion into the US pharmaceutical market was suspended after several cases of epileptic seizures in patients with bulimia who took the drug. When taking the standard form of bupropion in a dose not exceeding 450 mg / day, the likelihood of developing seizures is 0.33-0.44% (for comparison: when taking 100 mg / day of TCA, it is 0.1%, and with the intake of 200 mg / day TCA - 0.6-0.9%). Treatment with the standard form of bupropion begins with a dose of 75-100 mg / day, then it is increased to 150-450 mg / day. To reduce the risk of seizures with the use of the standard form of bupropion, more than 150 mg is recommended at one time, and the interval between doses should be at least 4 hours. A sustained-release form is usually given at 150 mg twice daily. The risk of epileptic seizures when taking this form is lower - perhaps because of a lower peak concentration of the drug. Recently, bupropion has been approved by the FDA for the treatment of nicotine addiction and is now marketed under the trade name "ziban".

Selective inhibitors of re-uptake

Currently, five drugs from the SSRI group are used: fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram. They are all effective in treating major depression. In addition, the effectiveness of some of them has been proven in dysthymia, a depressive episode of bipolar disorder, dysphoric disorder of the late luteal phase (premenstrual syndrome), panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and social phobia. It is assumed that all members of this class act by inhibiting the reuptake of serotonin by presynaptic endings. Although all SSRIs have more similarities than differences, and, apparently, the same mechanism of action, there are differences between them in the spectrum of side effects, the degree of interaction with other drugs, pharmacokinetics. The absence of the effect of one of the antidepressants of this group does not exclude the effectiveness of the other. Nevertheless, in many guidelines recommend in case of failure to switch to an antidepressant from another pharmacological group.

Fluoxetine. To date, fluoxetine is one of the most widely used antidepressants. His appearance in 1988 led to significant changes in the practice of therapy for depression. Currently, fluoxetine is approved for use in cases of major depression, obsessive-compulsive disorder, and bulimia. In addition, according to controlled studies, it is effective in a number of other affective and anxiety disorders, including dysphoric disorder of the late luteal phase (premenstrual syndrome) and panic disorder.

In contrast to TCAs, in which the dose-response curve is rather steep in depression, fluoxetine is flat in the dose range of 5 to 80 mg / day. Certain difficulties in interpreting this dependence are associated with a long half-life of fluoxetine and its primary metabolite, norfluoxetine, which is also capable of inhibiting the reuptake of serotonin. In fluoxetine, it is 1-3 days (at the beginning of treatment) and 4-6 days (with long-term admission). The half-elimination period of norfluoxetine, regardless of the duration of admission, is 4-16 days.

Placebo-controlled trials and comparative studies with other antidepressants, in which thousands of patients with depression participated, invariably demonstrated the benefits of fluoxetine. Fluoxetine does not cause side effects from the cardiovascular system, therefore it is safer than TCAs. Fluoxetine has no clinically significant effect on M-cholinergic receptors, histamine H1 receptors, alpha 1-adrenoreceptors, and serotonin 5-HT1 and 5-HT2 receptors, which explains the more favorable spectrum of side effects compared to TCAs. The most common side effects of fluoxetine include headache, irritability, insomnia, drowsiness, anxiety and tremors. Occasionally there are akathisia (a feeling of internal anxiety, diminishing in motor activity) and dystonia, which often occur when taking neuroleptics. Often there are side effects from the gastrointestinal tract: nausea, diarrhea, dry mouth, anorexia, dyspepsia. After the introduction of the drug into practice, it turned out that it does not often cause nausea, as noted in the registration studies. In addition, nausea can be minimized by taking the drug during or after a meal and lowering the initial dose in especially sensitive patients. As a rule, nausea is transient.

On the contrary, the frequency of sexual dysfunction in registration studies was lower than it turned out to be in practice. Perhaps this is due to the fact that in early studies, patients were not asked questions about such violations. SSRIs can cause a delayed onset of orgasm or anorgasmia, a decrease in libido. To correct this side effect, various measures have been proposed: dose reduction, medicinal vacations (for drugs with a relatively short half-elimation period), as well as additional prescription of buspirone, yohimbine, amantadine, cyproheptadine or bupropion.

The recommended initial dose of fluoxetine is 20 mg / day, although patients with increased sensitivity to its side effects may start at a lower dose. In many patients with depression or dysthymia, a dose of 20 mg / day restores the state of euthymia, but other patients need higher doses. Titrate the dose should be very slow, since the equilibrium state after the next increase in the dose is established after 40-80 days. If the antidepressant effect is reduced against the background of prolonged therapy with SSRIs, then it is often possible to increase it by increasing or decreasing the dose. To treat obsessive-compulsive disorder, higher doses of fluoxetine are often required than for the treatment of major depression.

Sertraline. It was the second SSRI, which was used in the US for the treatment of depression. It was also approved for the treatment of obsessive-compulsive and panic disorders. With the metabolism of sertraline, no active compounds are formed that have a therapeutic effect.

The effectiveness of sertraline in major depression has been demonstrated in a number of clinical trials. In a small study, it was noted that sertraline more effectively prevents repeated episodes of depression than fluvoxamine. A more extensive study showed that in the treatment of dysthymia sertraline at an average dose of 139.6 ± 58.5 mg / day is equivalent in its effect to imipramine in a dose of 198.8 ± 91.2 mg / day.

The most common side effects of sertraline are gastrointestinal disorders, such as nausea, diarrhea and dyspepsia. In addition, it often causes tremors, dizziness, insomnia, drowsiness, sweating, dry mouth, sexual dysfunction.

Treatment is recommended to begin with a dose of 50 mg / day. But many patients better tolerate the scheme with a lower initial dose: 25 mg / day for 4 days, then 50 mg / day for 5 days and further 100 mg / day. In a controlled blind study with flexible dosing in patients with depression, the average effective dose exceeded 100 mg / day, while many patients required a dose in the range of 100 to 200 mg / day.

Paroxetine. It is used in the US for the treatment of depression since 1993. Later, his other indications were also recorded: obsessive-compulsive and panic disorder. The efficacy of paroxetine for major depression was convincingly demonstrated in a series of double-blind, placebo-controlled studies. A comparison of the efficacy of different doses with large depression showed that paroxetine has a flat dose-effect curve in the dose range of 20 to 50 mg / day. Nevertheless, in some patients, increasing the dose leads to an increased effect. Comparative studies in outpatients showed that paroxetine is not inferior to imipramine, clomipramine, nefazodone and fluoxetine in effectiveness. Two comparative studies conducted in a hospital showed that paroxetine is not inferior in effectiveness to imipramine and amitriptyline. However, in another comparative study conducted in a hospital, paroxetine gave up clomipramine in effectiveness. In all comparative studies, paroxetine caused fewer side effects than TCAs. In a 12-month study, a stable effect with paroxetine was comparable to that of imipramine, but with TCA, the number of patients who left the study because of intolerable side effects was twice as high as with paroxetine.

The most common side effects of paroxetine are nausea, dry mouth, headache, asthenia, constipation, dizziness, insomnia, diarrhea, sexual dysfunction. It should be noted that the headache was very common in patients taking placebo. As with other SSRIs, nausea in paroxetine treatment can be reduced by taking the drug during or after a meal. In most patients, nausea is transient. The recommended initial dose of paroxetine is 20 mg / day. In patients who are particularly sensitive to its side effects, treatment should be started with a lower dose of 10 mg / day, and after 4 days it can be increased to 20 mg / day. Controlled clinical studies have shown that the minimum effective dose is 20 mg / day. If a higher dose is required, it is increased at an interval of 1 week.

Fluvoxamine. In the US it is used to treat obsessive-compulsive disorder. But, like other SSRIs, fluvoxamine is effective even in case of major depression. The therapeutic dose usually ranges from 100 to 250 mg / day.

Venlafaxine. Inhibits the reuptake of both serotonin and norepinephrine. According to some reports, the dysfunction of both noradrenergic and serotonergic systems is important in the pathogenesis of depression. Venlafaxine acts on both these systems, but it has no side effects inherent in TCAs, and does not require restrictions on the intake of other drugs and diet, as MAO inhibitors. In this regard, venlafaxine has a number of unique properties that distinguish it from other antidepressants. Unlike SSRIs, in the treatment of depression with venlafaxine, the dose-response curve is linear in nature, as in TCA.

As the outpatient trials showed, venlafaxine is not inferior in effectiveness to imipramine and trazodone. A clinical study performed in a hospital showed that venlafaxine (at an average dose of 200 mg / day) was superior to fluoxetine (at an average dose of 40 mg / day) after 4 and 6 weeks of therapy for effectiveness. In one study, it was shown that venlafaxine can be useful in treatment-resistant depression. In this study, depression was considered resistant to therapy when ineffective:

1. three different antidepressants, the effect of which was enhanced by auxiliaries, or
2. ECT and two different antidepressants with auxiliaries. At the 12th week of venlafaxine therapy, approximately 20% of patients had either a full effect (a Hamilton depression score of <9 points) or a partial effect (a reduction in the Hamiltonian depression score by at least 50%).

The spectrum of side effects of venlafaxine is similar to that of SSRIs, with the most common asthenia, sweating, nausea, constipation, anorexia, vomiting, drowsiness, dry mouth, dizziness, irritability, anxiety, tremor, accommodation, ejaculation / orgasm disorder and a decrease potency in men. Clinical experience of the drug showed that sexual dysfunction can occur in women. Many of these side effects, especially nausea, can be minimized if starting treatment with a lower dose than recommended in the drug instructions. Many patients tolerate venlafaxine well if the initial dose is 18.75 mg (half tablet 37.5 mg) twice daily. After 6 days, the dose is increased to 37.5 mg twice a day. The effective dose of venlafaxine ranges from 75 to 375 mg / day.

Currently, a delayed-release form of venlafaxine (XR) is available in the form of capsules containing 37.5 mg, 75 mg, and 150 mg of the active substance. Treatment with this drug begins with a dose of 37.5 mg / day, a week later it is increased to 75 mg / day. The range of effective doses in this case is probably the same as when taking the usual form of venlafaxine, although in clinical trials, venlafaxine XR was tested at doses not exceeding 225 mg / day. The form with delayed release less often causes side effects than the usual form of venlafaxine.

Nefazodone (serzon) is an antidepressant that is close to trazodone in its chemical structure. Nefazodone is a weak inhibitor of the reuptake of serotonin and norepinephrine, as well as a serotonin 5-HT 2 -receptor antagonist. In addition, nefazodone blocks alpha1-adrenergic receptors, thereby causing orthostatic hypotension. Apparently, nefazodone does not have a clinically significant effect on alpha1 and beta adrenoreceptors, M-cholinergic receptors, 5-HT1A receptors, dopamine receptors, and GABA receptors. In the metabolism of nefazodone, a number of active compounds are formed, including hydroxynephazodone (which is close in pharmacological properties to the parent compound), metachlorophenylpiperazine (mCPP), a 5-HT agonist, in - and 5-HT1C receptors and a 5-HT2- antagonist 5-HT3 receptors, as well as the triazolidione metabolite, whose properties are poorly understood. The concentration of nefazodone in plasma reaches an equilibrium state in 4-5 days, while nefazodone and hydroxynephazodone accumulate in a concentration that is 2-4 times higher than the concentration after a single dose of the drug. Receiving nefazodone during a meal slows its absorption, as a result of which the peak concentration of the drug in the plasma can be reduced by 20%.

In the US, nefazodone has been approved by the FDA as a drug for treating major depression. Its effectiveness in major depression has been proven in placebo-controlled studies. The average therapeutic dose in the treatment of major depression is 400-600 mg / day, it is divided into two doses. Outpatient treatment is recommended starting at a dose of 50 mg 2 times a day, then it is increased every 4-7 days.

The most common side effects of nefazodone are: drowsiness, dry mouth, nausea, dizziness, constipation, asthenia, confusion, violation of accommodation.

Nefazadone inhibits the activity of cytochrome P450 3A and can interact with drugs that are the substrate of this enzyme. In addition, it interacts with those drugs that bind to plasma proteins. Therefore, manufacturers do not recommend combining nefazodone with terfenadine (seldane), astemisole (gismanalom), cisapride (propulsion). With simultaneous admission with digoxin in young men, nefazadone increases its maximum and minimum concentrations by 29 and 27%, respectively, while the area under the concentration-time curve (AUC) increases by 15%. Caution should be combined with nefazadonom triazol (haltsion) and alprazolam (ksanaks), because it inhibits the metabolism of benzodiazepines. With nefazadonom it is impossible to combine MAO inhibitors. When switching from MAO inhibitors to nefazadone (or vice versa), a sufficiently long washing period is necessary. Nefazodone is available in tablets of 100 mg, 150 mg, 200 mg and 250 mg.

Mirtazapine (remeron) is a tetracyclic antidepressant having a piperazino-azepine structure. The therapeutic effect of mirtazapine is explained by the increase in noradrenergic and serotonergic transmission in the central nervous system. In the experiment it was shown that mirtazapine blocks alpha 1-adrenergic receptors, which leads to an increase in the release of norepinephrine and serotonin from nerve endings. In addition, mirtazapine is an antagonist of 5-HT2 and 5-HT3 receptors, but does not affect 5-HT1A and 5-HT1B receptors. The blockade of histamine Hj receptors is probably the cause of the pronounced sedative effect that occurs when lower doses are administered. Orthostatic hypotension is relatively rare and may be due to the moderate adrenoblocking effect of the drug on the periphery.

The peak concentration of mirtazapine in plasma is achieved 2-4 hours after administration. The half-elimination period is 20-40 hours. Metabolism of mirtazapine occurs by demethylation and hydroxylation, followed by conjugation with glucuronide. Hydroxylation is carried out by the isoenzymes 1A2 and 2D6 of the cytochrome P450 system, while the isoenzyme ZA catalyzes the formation of N-desmethyl and N-oxide metabolites. In the dose range from 15 to 80 mg / day there is a linear relationship between the dose and the concentration of the drug in the plasma. The average half-elimination period of mirtazepine is longer in women (37 hours) than in men (26 hours), although the clinical significance of this difference is not determined.

The efficacy of mirtazapine in major depression was demonstrated in four placebo-controlled studies conducted in adult outpatients. The average effective dose in these studies ranged from 21 to 32 mg / day. The most common side effects of mirtazapine are: drowsiness, increased appetite, weight gain, dizziness. In 15% of patients taking mirtazepine, a rise in cholesterol levels after eating is more than 20% (compared with the norm). In registration studies, two of the 2,796 patients had agranulocytosis, and the third patient had neutropenia. Martazapine can not be combined with MAO inhibitors, and when switching from it to MAO inhibitors (or vice versa), a sufficiently long washing period is needed. While there is no data on the clinically significant interaction of mirtazapine with the cytochrome P450 system, this issue has not been adequately studied.

Mirtazapine is available in tablets of 15 mg and 30 mg. The initial dose is usually 15 mg / day, subsequently it is increased every 7-14 days. If at a dose of 7.5-15 mg / day there is drowsiness, it often passes after increasing the dose to 30-45 mg / day. In elderly people, as well as in diseases of the liver and kidneys, the dose of mirtazapine should be reduced.

Pharmacokinetics and drug interaction

Antidepressants of the new generation differ significantly in the duration of the half-elimination period (it varies from several hours to several days) and the degree of binding to plasma proteins.

The possibility of drug interaction between antidepressants of a new generation and other drugs attracts increasing attention. However, there is still insufficient information on the clinical significance and frequency of interaction of these funds. With the use of antidepressants, two types of drug interactions are especially common: displacement of other drugs from compounds with plasma proteins and inhibition of cytochrome P450. Induction of cytochrome P450 enzymes under the influence of antidepressants is observed less often. In plasma, drugs are non-specifically associated primarily with albumin or acid alpha-1-glycoproteins. When the substance is displaced from the bond with proteins, the concentration of the active drug is increased, which can lead to an enhanced effect at the same dose. Even more data on drug interactions due to inhibition of cytochrome P450 enzymes.

The presence of drug interactions should be considered when treatment or side effects occur at a lower dose than usual. Some drug interactions do not appear clinically and remain unnoticed until they lead to serious complications. Ultimately, pharmacokinetic interactions lead to pharmacodynamic results.

The clinical significance of cytochrome P450 inhibition depends on a number of factors. The risk factors for drug interactions are the reception of a large number of different drugs, a violation of kidney and liver function, and age. The risk factors are also the intake of active inhibitors of cytochrome P450, such as quinidine and ketoconazole. Awareness of possible drug interactions and their careful monitoring is the optimal tactic for increasing the effectiveness of treatment and reducing the likelihood of side effects.