Depression - Medications (antidepressants)

Pharmacological treatment of depression

The effectiveness of antidepressants in major depression has been proven in numerous placebo-controlled studies, which together have involved tens of thousands of patients. On average, antidepressants are effective in 55-65% of patients. Over the past decade, the arsenal of drugs for treating depression has expanded significantly. Significant progress has been made in developing new drugs that are safer and more tolerable.

Read also: 8 Things You Need to Know About Antidepressants

In the early 20th century, the main treatment for major depression was "shock" therapy, which involved administering insulin, which caused hypoglycemia, or horse serum. In the 1930s, ECT was introduced, which was a major advance in this field. ECT is still considered a very effective and safe treatment for major depression. Along with other methods, this method is used for severe depression, depression with psychotic symptoms, mixed episodes of bipolar disorder, and when there is an immediate threat to life due to suicidal intent or refusal to eat or drink.

In the 1940s and 1950s, psychostimulants (eg, D-amphetamine and methylphenidate) were used as antidepressants, but their use was limited by side effects. Psychostimulants are still used as adjuvants (to enhance the effect of antidepressants) and sometimes as monotherapy in elderly or somatically debilitated patients, although their effectiveness has not been proven in controlled trials. A major breakthrough in the pharmacotherapy of major depression occurred in the mid-1950s, when iproniazid, a monoamine oxidase inhibitor (MAOI) used to treat tuberculosis, was accidentally discovered to have mood-elevating properties. Similar properties were found in imipramine, which was developed as an alternative to the neuroleptic chlorpromazine. However, the drug turned out to have no antipsychotic properties, but can be used as an antidepressant. Imipramine was introduced into the United States for the treatment of depression in 1988. Over the next few years, a series of new tricyclic antidepressants (TCAs) appeared, which had similar pharmacological and clinical effects. The secondary amine TCAs (such as desipramine, a metabolite of imipramine, or nortriptyline, a metabolite of amitriptyline) were safer than the tertiary amines, but they could still cause a number of serious side effects. Trazodone was introduced into clinical practice in 1982 and was widely used until the first selective serotonin reuptake inhibitor, fluoxetine (Prozac), appeared in 1988. Fluoxetine was the first SSRI approved by the FDA for the treatment of depression. However, five years earlier, another SSRI, fluvoxamine (Luvox), had been introduced in Switzerland. SSRIs revolutionized the treatment of major depression because they caused significantly fewer side effects and were more convenient to use, not requiring such a long dose titration as TCAs and MAOIs.

The importance of SSRIs has transcended the medical realm, becoming an integral part of American culture and raising questions about their use. These drugs have increased public awareness that severe mental illness has biological roots, and have de-stigmatized psychiatric diagnosis and the need for treatment by a psychiatrist. At the same time, questions have arisen about whether antidepressants are being overprescribed and whether drug therapy is crowding out other effective treatments for mental disorders.

In 1993, four years after fluoxetine, sertraline (Zoloft), followed by paroxetine (Paxil), were approved by the FDA for use in the treatment of major depression. The FDA later approved the use of these two drugs for panic disorder and obsessive-compulsive disorder (OCD). Fluvoxamine was approved for use in the United States only for OCD, but it is also used in many countries to treat depression. Somewhat later, another SSRI, citalopram (cipramil), became widely used.

Recently, so-called atypical antidepressants, which differ in their mechanism of action from SSRIs, have been introduced into clinical practice. Bupropion (Wellbutrin), a monocyclic aminoketone, first appeared on the pharmaceutical market in 1989. However, its mechanism of action remains unclear to this day. Venlafaxine (Effexor), a dual reuptake inhibitor (of both serotonin and norepinephrine), is similar in its 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 pharmacologically related to trazodone, is a weak serotonin and norepinephrine reuptake inhibitor and a potent 5-HT 2 receptor antagonist. The most recently approved antidepressant is mirtazapine (Re-meron), a 5-HT2 and 5-HT3 receptor antagonist and an alpha 2 adrenergic receptor agonist. Many countries (but not 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 becomes relapsing, but it is impossible to predict its further course at the onset of depression.

When choosing a drug that can be prescribed for many years, it is necessary to consider its effectiveness, side effects, possible interactions with other drugs, the cost of the drug and its mechanism of action. The goal of treatment is to restore a state of complete euthymia, and not just to alleviate symptoms, which can only be regarded as a partial therapeutic effect. The effect of monotherapy with the first drug chosen may be insufficient to achieve the goal in the long term, but before moving on to combination therapy, an attempt should be made to find a drug that would have the desired effect as monotherapy.

Potential side effects of antidepressants are a constant source of concern for both the patient and the physician. Many of them can be predicted by knowing the drug's interactions with different types of receptors.

However, sometimes side effects have a positive effect. For example, in a patient with 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 with dementia, the anticholinergic effect of the drug will worsen cognitive impairment. Orthostatic hypotension is more dangerous for elderly women with osteoporosis (since they can break a hip if they fall) than for younger patients. One of the main problems associated with long-term use of TCAs is the possibility of weight gain, which can be significant. Patients with difficulty falling asleep are often tempted to use an antidepressant with a strong sedative effect, but it must be remembered that this is only one manifestation of depression, and therefore the disease as a whole must be treated, not its individual symptoms. Thus, for a patient suffering from insomnia, such treatment may initially help, but then, as the depression weakens, problems associated with difficulty waking up in the morning will arise.

Drug interactions are possible between antidepressants and drugs from other groups. This usually occurs through inhibition of cytochrome P450 enzymes that carry out metabolic degradation of other drugs, and by displacing the other drug from its protein binding. Drug interactions are discussed in more detail below.

The cost of treatment is relevant not only for patients, but also for doctors and the healthcare system. Generic TCAs are much cheaper (per tablet) than new-generation antidepressants. However, it should be taken into account that the cost of the drug is only 4-6% of the cost of outpatient treatment, and the use of more modern drugs that are safer and provide higher patient adherence to treatment (compliance) ultimately leads to lower treatment costs.

There are several stages of treatment for major depression. According to Kupfer (1991), acute, continued and maintenance stages of treatment are distinguished. The acute stage is the beginning of treatment in the symptomatic phase of the disease. It involves diagnosis, prescription of medications and titration of their dose. The duration of this stage is usually measured in weeks. As soon as significant improvement or remission has been achieved, the continued stage begins, which lasts 4-9 months. An episode of depression that develops at this stage is considered a relapse and is usually assessed as a continuation of the same episode for which treatment was started in the acute stage. By the end of this stage, the patient is in a state of remission after this completed depressive episode. Maintenance therapy is administered to patients who need continued treatment. Its duration is not limited, the goal is to prevent the development of a new episode. Maintenance therapy is indicated for recurrent major depression, especially in cases where the patient has already suffered three or more depressive episodes of any severity or at least two severe episodes. If symptoms worsen during maintenance therapy, it is considered a new episode of depression, not a relapse of the old one.

Antidepressant nomenclature. Groups of antidepressants are named according to their mechanism of action (e.g. MAO inhibitors or SSRIs) or chemical structure (e.g. TCAs or heterocyclic antidepressants). The effect of most antidepressants is associated with the impact on the noradrenergic, serotonergic or dopaminergic systems. Antidepressants differ in the intensity of inhibition of the reuptake of different monoamines.

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

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Tricyclic antidepressants

Over the past thirty years, the efficacy of tricyclic antidepressants has been repeatedly confirmed in placebo-controlled trials. Before the advent of newer generation antidepressants, tricyclic antidepressants were the drugs of choice, and drugs such as imipramine or amitriptyline are still considered the "gold standard" of treatment in many studies. It is assumed that the main mechanism of action of tricyclic antidepressants is the inhibition of the reuptake of norepinephrine by presynaptic endings in the brain, although drugs in this group also inhibit the reuptake of serotonin. An exception is clomipramine (Anafranil), which is a more potent and selective inhibitor of serotonin reuptake than other tricyclic antidepressants. Clomipramine is used in the USA mainly for the treatment of obsessive-compulsive disorder, but in European countries it has also been used for many years as an antidepressant. Tricyclic antidepressants, which are secondary amines, inhibit norepinephrine reuptake more selectively than their tertiary precursors. It is suggested that inhibition of norepinephrine reuptake is the cause of behavioral activation and arterial hypertension in some patients taking tricyclic antidepressants.

Tricyclic antidepressants are the only class of antidepressants that show a relationship between serum drug levels and antidepressant activity. The therapeutic plasma concentration of imipramine is greater than 200 ng/mL (including imipramine and desipramine). In contrast, nortriptyline has a therapeutic window of 50–150 ng/mL; above or below these levels, its antidepressant effect is reduced.

The side effects of tricyclic antidepressants may limit their use in some patients. Some of these can be alleviated by starting treatment with a low dose and gradually increasing it. The sedative effect usually resolves with long-term use, while orthostatic hypotension usually does not improve over time. Abrupt withdrawal of TCAs should be avoided because of the risk of a rebound effect caused by the cessation of anticholinergic action, which manifests itself as insomnia and diarrhea. A more serious problem is that, compared with many newer-generation antidepressants, tricyclic antidepressants have a low therapeutic index and adverse effects on the heart. Overdose with a single 7- to 10-day dose of the drug can be fatal. Cardiotoxicity in overdose is due to the blockade of fast sodium channels, which is typical of type 1a antiarrhythmics.

Treatment is usually initiated with 25-50 mg/day of amitriptyline, desipramine, or imipramine or 10-25 mg/day of nortriptyline. In the presence of comorbid panic disorder, the lower end of the indicated dosage range should be followed, since such patients are very sensitive to side effects. The dose is gradually increased over 7-14 days to the lower therapeutic dose. After 2-3 weeks, a further increase in the dose is possible. In children and individuals over 40 years of age, an ECG should be performed before prescribing tricyclic antidepressants. However, many clinicians perform an ECG in all patients for whom tricyclic antidepressants are considered.

Considerable information has been accumulated regarding approaches to dosing TCAs in maintenance therapy and their efficacy in recurrent depression. Contrary to the practice of using relatively high doses in the acute phase of treatment and lower doses in the maintenance phase, studies with TCAs show that the dose that has proven effective in the acute phase should be subsequently maintained in continued and maintenance therapy. Long-term therapy with TCAs has been shown to be effective in recurrent depression. In one study, patients with an average number of major depressive episodes of 4.2, with two episodes occurring in the past 4 years, were selected. All subjects were prescribed therapeutic doses of imipramine. Patients with a good response to treatment were randomized. Eighty percent of patients who continued to take imipramine at the initial therapeutic dose after randomization had no relapses for 3 years. In the same group where patients took placebo after randomization, 90% of them developed relapses or new depressive episodes.

Although amoxapine and maprotiline are tetracyclic antidepressants, they are similar to TCAs in many ways. Maprotiline is a norepinephrine reuptake inhibitor. Amoxapine is metabolized to form the neuroleptic loxapine, so it can simultaneously affect both affective and psychotic disorders. However, since it is a kind of combination of an antidepressant and an antipsychotic with a fixed ratio of their activity, it is usually not the drug of choice, since it is impossible to individually adjust the dose of the metabolite with antipsychotic activity. In addition, with long-term treatment with amoxapine, there is a risk of developing tardive dyskinesia.

Clomipramine is a tricyclic antidepressant with a unique pharmacological action. Unlike other tricyclic antidepressants, clomipramine is a more selective inhibitor of serotonin reuptake (approximately 5 times more potent than norepinephrine). Many consider it a "mixed reuptake inhibitor" that has some advantages in the treatment of the most severe cases of depression. However, not everyone shares this view. The Antidepressant Research Group at the University of Denmark compared the efficacy of clomipramine with that of paroxetine or citalopram in two different studies. According to the results of these studies, clomipramine, a mixed reuptake inhibitor, was superior to both SSRIs. In another study, which compared the efficacy of imipramine and paroxetine, no significant differences were found, although the average dose of imipramine (150 mg/day) may have been too low. A hospital comparison of the efficacy of fluoxetine and imipramine revealed no differences.

Tricyclic antidepressants have some advantages over newer-generation antidepressants, including well-proven efficacy, more than 35 years of use, lower cost per pill, and the ability to take the drug once a day. However, they are significantly inferior due to side effects and relatively low safety. Tricyclic antidepressants still play an important role in the treatment of major depression, although they are no longer the first-line drugs.

Monoamine oxidase inhibitors

In the United States, mainly irreversible nonselective MAO inhibitors are currently used, blocking both MAO-A and MAO-B. In other countries, reversible and more selective drugs such as moclobemide are used. Because these drugs selectively act on only one isoform of the enzyme, their use does not require dietary restrictions, which were necessary when using earlier drugs in this group. MAO inhibitors are currently represented on the US pharmaceutical market by three drugs: phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan). All of them inhibit MAO-A, which metabolizes norepinephrine, serotonin, and epinephrine, and MAO-B, which metabolizes phenylethylamine, phenylethanolamine, tyramine, and benzylamine. Dopamine is a substrate for both isoforms of the enzyme, but in the CNS it is metabolized primarily by MAO-B.

The therapeutic effect of MAO inhibitors is proportional to their ability to inhibit platelet MAO activity. The therapeutic dose of phenelzine is usually 45-90 mg/day, tranylcypromine - 10-30 mg/day, isocarboxazid - 30-50 mg/day. Treatment with phenelzine is often initiated with a dose of 15 mg/day for 2-4 days, then increased to 30 mg/day, and then added by 15 mg each week. Treatment with tranylcypromine is usually initiated with a dose of 10 mg/day for 2-4 days, then increased to 20 mg/day, and after 7 days the dose may be further increased. The initial dose of isocarboxazid is usually 10 mg/day, then increased to 30-50 mg/day.

Side effects of MAO inhibitors include orthostatic hypotension, drowsiness, insomnia, edema, tachycardia, palpitations, sexual dysfunction, and weight gain. Weight gain and edema are more pronounced with phenelzine, an MAO inhibitor from the hydrazine group, than with tranylcypromine. To correct orthostatic hypotension, it is recommended to increase water and salt intake, wear elastic stockings, and prescribe fludrohydrocortisone (florinef) or small doses of caffeine.

Because of the potential for adverse interactions with tyramine-containing foods and some cold remedies, MAO inhibitors are not the drugs of choice for depression. When taking MAO inhibitors, tyramine-rich foods should be avoided. Therefore, foods that are aged and fermented for long periods of time (e.g., many cheeses, smoked foods, pickles, yeast, and many wines and beers), most cold remedies, dextromethorphan, meperidine, and epinephrine, often used with local anesthetics, are contraindicated. Some patients can break their diet without serious consequences, but they should be reminded that the tyramine content of even a single piece of cheese can vary widely, and that possible consequences include an increased risk of stroke and myocardial infarction. Many clinicians prescribe nifedipine (10 mg) or chlorpromazine (100 mg) to patients in advance, which the patient should take when a severe headache occurs, and then seek immediate medical attention.

MAO inhibitors are effective antidepressants. Their effectiveness has been proven in major depression, depression with atypical symptoms, depression in bipolar disorder, and two anxiety disorders - panic disorder and social phobia.

Trazodone. Trazodone is a triazolopyridine and differs from other antidepressants in its chemical properties and mechanism of action. Unlike TCAs, trazodone has virtually no anticholinergic or antiarrhythmic properties, making it attractive for the treatment of depression. Doses of 400-600 mg/day are usually required for the treatment of depression, but when taking this dose, many patients experience severe 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 (the daily dose is divided into several doses).

A rare but serious side effect is priapism, which occurs in an average of 1 in 6,000 men. Any manifestation of erectile dysfunction, such as an erection that lasts too long or occurs in an inappropriate situation, should promptly promptly be examined. Currently, given its sedative properties, trazodone is often used in combination with SSRIs for persistent insomnia. For this purpose, 25-100 mg of trazodone is usually prescribed 30-60 minutes before bedtime.

Bupropion. Bupropion is a compound from the aminoketone group, is a weak inhibitor of dopamine and norepinephrine reuptake, but does not affect serotonin reuptake. It is usually taken three times a day, or twice a day when using the recently introduced slow-release form. Unlike other antidepressants, in particular SSRIs, bupropion does not affect sexual function, which is its great advantage. In addition, bupropion does not have an anticholinergic effect, and weight gain is very rare when taking it. There is evidence that bupropion is less likely to provoke a transition from depression to mania in patients with bipolar disorder.

Bupropion was withdrawn from the US pharmaceutical market after several cases of epileptic seizures in patients with bulimia who were taking the drug. When taking the standard form of bupropion at a dose not exceeding 450 mg/day, the probability of developing seizures is 0.33-0.44% (for comparison: when taking 100 mg/day of TCAs, it is 0.1%, and when taking 200 mg/day of TCAs - 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 when using the standard form of bupropion, it is recommended to take more than 150 mg at a time, while the interval between doses should be at least 4 hours. The slow-release form is usually prescribed at 150 mg twice a day. The risk of seizures is lower with this form, possibly due to a lower peak concentration of the drug. Bupropion was recently approved by the FDA for the treatment of nicotine addiction and is now marketed under the trade name Zyban.

Selective reuptake inhibitors

There are five drugs in the SSRI group currently in use: fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. All are effective in the treatment of major depression. Some have also been shown to be effective in dysthymia, major depressive episode of bipolar disorder, late luteal phase dysphoric disorder (premenstrual syndrome), panic disorder, posttraumatic stress disorder, obsessive-compulsive disorder, and social phobia. All are thought to act by inhibiting the reuptake of serotonin by presynaptic terminals. Although all SSRIs have more similarities than differences and appear to have the same mechanism of action, they differ in their side effects, drug interactions, and pharmacokinetics. The lack of effect of one antidepressant in this group does not preclude the effectiveness of another. However, many guidelines recommend switching to an antidepressant from another pharmacological group in case of failure.

Fluoxetine. Fluoxetine is one of the most widely used antidepressants today. Its introduction in 1988 led to significant changes in the practice of treating depression. Fluoxetine is currently approved for use in 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 late luteal phase dysphoric disorder (premenstrual syndrome) and panic disorder.

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

Placebo-controlled trials and comparative studies with other antidepressants, which involved thousands of patients with depression, have consistently demonstrated the advantages of fluoxetine. Fluoxetine does not cause side effects from the cardiovascular system, so it is safer than TCAs. Fluoxetine does not have a clinically significant effect on M-cholinergic receptors, histamine H1 receptors, alpha1-adrenergic receptors, as well as 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 tremor. Akathisia (a feeling of internal restlessness that decreases with motor activity) and dystonia, which often occur when taking neuroleptics, are rare. Side effects from the gastrointestinal tract are common: nausea, diarrhea, dry mouth, anorexia, dyspepsia. After the drug was introduced into practice, it turned out that it does not cause nausea as often as was noted in registration studies. In addition, nausea can be minimized if the drug is taken during or after meals and the initial dose is reduced in patients who are particularly sensitive to it. 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. This may be due to the fact that in early studies patients were not asked about such disorders. SSRIs can cause delayed onset of orgasm or anorgasmia, decreased libido. Various measures have been proposed to correct this side effect: dose reduction, drug holidays (for drugs with a relatively short half-life), and additional administration of buspirone, yohimbine, amantadine, cyproheptadine or bupropion.

The recommended starting dose of fluoxetine is 20 mg/day, although patients who are hypersensitive to its side effects may start with a lower dose. In many patients with depression or dysthymia, a dose of 20 mg/day restores euthymia, but other patients require higher doses. The dose should be titrated very slowly, since steady state after each dose increase is established after 40-80 days. If the antidepressant effect decreases during long-term SSRI therapy, it can often be enhanced by increasing or decreasing the dose. Higher doses of fluoxetine are often required for the treatment of obsessive-compulsive disorder than for major depression.

Sertraline. Was the second SSRI to be used in the United States for the treatment of depression. It was also approved for the treatment of obsessive-compulsive disorder and panic disorder. Sertraline is not metabolized to form active compounds with therapeutic effects.

Sertraline has been shown to be effective in major depression in a number of clinical trials. A small study found that sertraline was more effective than fluvoxamine in preventing recurrent episodes of depression. A larger study found that sertraline at a mean dose of 139.6 ± 58.5 mg/day was equivalent to imipramine at a dose of 198.8 ± 91.2 mg/day in treating dysthymia.

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

Treatment is recommended to begin with a dose of 50 mg/day. However, many patients tolerate a lower initial dose regimen better: 25 mg/day for 4 days, then 50 mg/day for 5 days, and then 100 mg/day. In a controlled, blinded, flexible-dose study in patients with depression, the average effective dose exceeded 100 mg/day, with many patients requiring a dose in the range of 100 to 200 mg/day.

Paroxetine. It has been used in the USA for the treatment of depression since 1993. Later, other indications were registered: obsessive-compulsive and panic disorders. The effectiveness of paroxetine in major depression has been convincingly proven in a series of double-blind, placebo-controlled studies. Comparison of the effectiveness of different doses in major depression showed that paroxetine has a flat dose-effect curve - in the dose range from 20 to 50 mg / day. However, in some patients, increasing the dose leads to an increase in the effect. Comparative studies in outpatients have shown that paroxetine is not inferior in effectiveness to imipramine, clomipramine, nefazodone and fluoxetine. Two comparative studies conducted in a hospital setting have shown that paroxetine is not inferior in effectiveness to imipramine and amitriptyline. However, in another comparative study conducted in a hospital setting, paroxetine was inferior to clomipramine in efficacy. In all comparative studies, paroxetine caused fewer side effects than the TCAs. In a 12-month study, the sustained effect of paroxetine was comparable to that of imipramine, but the TCAs had twice the number of withdrawals due to intolerable side effects as paroxetine.

The most common side effects of paroxetine are nausea, dry mouth, headache, asthenia, constipation, dizziness, insomnia, diarrhea, and sexual dysfunction. It should be noted that headache was also very common in patients taking placebo. As with other SSRIs, nausea during paroxetine treatment can be reduced by taking the drug during or after meals. 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, it is better to start treatment with a lower dose of 10 mg/day, and after 4 days it can be increased to 20 mg/day. Controlled clinical trials have shown that the minimum effective dose is 20 mg/day. If a higher dose is required, it is increased at intervals of 1 week.

Fluvoxamine. In the United States, it is used to treat obsessive-compulsive disorder. But like other SSRIs, fluvoxamine is also effective in 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 data, dysfunction of both the noradrenergic and serotonergic systems is important in the pathogenesis of depression. Venlafaxine affects both of these systems, but it is devoid of the side effects characteristic of TCAs and does not require restrictions in taking other drugs and diet, as do MAO inhibitors. In this regard, venlafaxine has a number of unique properties that distinguish it from other antidepressants. Unlike SSRIs, when treating depression with venlafaxine, the dose-effect curve is linear, as with TCAs.

Outpatient trials have shown that venlafaxine is as effective as imipramine and trazodone. A clinical study conducted in an inpatient setting showed that venlafaxine (at an average dose of 200 mg/day) was more effective than fluoxetine (at an average dose of 40 mg/day) after 4 and 6 weeks of therapy. One study showed that venlafaxine may be useful in treatment-resistant depression. In this study, depression was considered treatment-resistant if:

1. three different antidepressants, the action of which was enhanced by adjuvants, or
2. ECT and two different antidepressants with adjuvants. At week 12 of venlafaxine therapy, approximately 20% of patients showed either a complete response (Hamilton Depression Rating Scale score < 9) or a partial response (reduction in Hamilton Depression Rating Scale score by at least 50%).

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

An extended-release form of venlafaxine (effexor XR) is now available as capsules containing 37.5 mg, 75 mg, and 150 mg of the active substance. Treatment with this drug is initiated at a dose of 37.5 mg/day, which is increased to 75 mg/day after one week. The effective dose range in this case is probably the same as with the regular form of venlafaxine, although venlafaxine XR has been tested in clinical trials at doses up to 225 mg/day. The extended-release form causes fewer side effects than the regular form of venlafaxine.

Nefazodone (Serzone) is an antidepressant similar to trazodone in its chemical structure. Nefazodone is a weak serotonin and norepinephrine reuptake inhibitor and 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-adrenergic receptors, M-cholinergic receptors, 5-HT1A receptors, dopamine receptors, and GABA receptors. Nefazodone is metabolized to form a number of active compounds, including hydroxynefazodone (which is similar in its pharmacological properties to the parent compound), metachlorophenylpiperazine (mCPP), which is a 5-HT, β- and 5-HT1C-receptor agonist and a 5-HT2- and 5-HT3-receptor antagonist, and a triazoledione metabolite, the properties of which are poorly understood. Plasma nefazodone concentrations reach steady state within 4-5 days, with nefazodone and hydroxynefazodone accumulating to concentrations 2-4 times higher than those seen after a single dose of the drug. Taking nefazodone with food slows its absorption, resulting in a 20% decrease in peak plasma concentrations.

In the United States, nefazodone has received FDA approval as a drug for the treatment of major depression. Its effectiveness in major depression has been proven in placebo-controlled studies. The average therapeutic dose for the treatment of major depression is 400-600 mg/day, divided into two doses. Outpatient treatment is recommended to begin with a dose of 50 mg 2 times a day, then it is increased every 4-7 days.

The most common side effects of nefazodone include: drowsiness, dry mouth, nausea, dizziness, constipation, asthenia, confusion, and accommodation disorder.

Nefazodone inhibits the activity of cytochrome P450 3A and may interact with drugs that are substrates of this enzyme. In addition, it interacts with those drugs that bind to plasma proteins. Therefore, manufacturers do not recommend combining nefazodone with terfenadine (seldan), astemizole (gismanal), cisapride (propulsid). When taken simultaneously with digoxin in young men, nefazodone increases its maximum and minimum concentration by 29 and 27%, respectively, while the area under the concentration-time curve (AUC) increases by 15%. Triazole (halcion) and alprazolam (xanax) should be combined with nefazodone with caution, since they inhibit the metabolism of benzodiazepines. MAO inhibitors cannot be combined with nefazodone. When switching from MAO inhibitors to nefazodone (or vice versa), a fairly long washout period is required. Nefazodone is available in tablets of 100 mg, 150 mg, 200 mg and 250 mg.

Mirtazapine (Remeron) is a tetracyclic antidepressant with a piperazine-azepine structure. The therapeutic effect of mirtazapine is explained by the enhancement of noradrenergic and serotonergic transmission in the central nervous system. In an experiment, mirtazapine was shown to block alpha1-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 act on 5-HT1A- and 5-HT1B-receptors. Blockade of histamine H1-receptors is probably the cause of the pronounced sedative effect that occurs when taking lower doses of the drug. Orthostatic hypotension is observed relatively rarely and may be due to the moderate alpha-adrenergic blocking effect of the drug on the periphery.

Mirtazapine peak plasma concentrations are reached 2-4 hours after administration. The half-life is 20-40 hours. Mirtazapine is metabolised by demethylation and hydroxylation followed by glucuronide conjugation. Hydroxylation is mediated by cytochrome P450 isoenzymes 1A2 and 2D6, while isoenzyme 3A catalyses the formation of N-desmethyl and N-oxide metabolites. There is a linear relationship between dose and plasma drug concentration in the dose range of 15 to 80 mg/day. The mean half-life of mirtazapine is longer in women (37 hours) than in men (26 hours), although the clinical significance of this difference has not been determined.

Mirtazapine efficacy in major depression has been demonstrated in four placebo-controlled studies in adult outpatients. The mean effective dose in these studies ranged from 21 to 32 mg/day. The most common adverse effects of mirtazapine include drowsiness, increased appetite, weight gain, and dizziness. Fifteen percent of patients taking mirtazapine experienced a more than 20% increase in cholesterol after meals (compared to normal). In registration studies, two of 2,796 patients developed agranulocytosis and a third patient developed neutropenia. Martazapine should not be combined with MAO inhibitors, and a fairly long washout period is required when switching from it to MAO inhibitors (or vice versa). There are no data on clinically significant interactions of mirtazapine with the cytochrome P450 system, and this issue has not been sufficiently studied.

Mirtazapine is available in tablets of 15 mg and 30 mg. The initial dose is usually 15 mg/day, then it is increased every 7-14 days. If drowsiness is observed at a dose of 7.5-15 mg/day, it often goes away after increasing the dose to 30-45 mg/day. In elderly people, as well as in cases of liver and kidney disease, the dose of mirtazapine should be reduced.

Pharmacokinetics and drug interactions

New generation antidepressants 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 interactions between new-generation antidepressants and other drugs is attracting increasing attention. However, there is still insufficient information on the clinical significance and frequency of interactions between these drugs. Two types of drug interactions are particularly common with antidepressants: displacement of other drugs from plasma protein binding and cytochrome P450 inhibition. Induction of cytochrome P450 enzymes by antidepressants is less common. In plasma, drugs bind nonspecifically primarily to albumin or acidic alpha1-glycoproteins. When a substance is displaced from protein binding, the concentration of the active drug increases, which may lead to an increased effect at the same dose. There are even more data on drug interactions resulting from inhibition of cytochrome P450 enzymes.

Drug interactions should be considered when therapeutic or adverse effects occur at a lower than usual dose. Some drug interactions are not clinically evident and go unnoticed until they cause serious complications. Ultimately, pharmacokinetic interactions lead to pharmacodynamic results.

The clinical significance of cytochrome P450 inhibition depends on a number of factors. Risk factors for drug interactions include taking a large number of different drugs, impaired renal and hepatic function, and age. Risk factors also include taking active cytochrome P450 inhibitors such as quinidine and ketoconazole. Awareness of possible drug interactions and their careful monitoring is the optimal tactic for improving treatment outcomes and reducing the likelihood of side effects.