Selective serotonin reuptake inhibitors

Currently, for the treatment of depression, especially in outpatient practice, relatively new antidepressants are used - selective serotonin reuptake inhibitors (SSRIs), which have significantly fewer side effects than tricyclic antidepressants due to a selective effect on serotonin metabolism (selective inhibition of 5- NT).

SSRIs are represented by drugs such as: fluoxetine (Prozac), fluvoxamine (Fevarin), sertraline (Zoloft, Stimuloton, Asentra), paroxetine (Paxil, Rexetine), cipramil (Citalopram, Cipralex).

Unlike TCAs, a feature of the action of serotonergic antidepressants is their selective effect on the serotonergic system, initially identified in laboratory studies (Wong D., et al., 1974; Fuller R., et al., 1977). The effectiveness of SSRI therapy for depression is at least 65% (Mulrow D., et al., 2000)

Due to the affinity of these drugs and their active metabolites for serotonin receptors, serotonin reuptake is blocked at the level of presynaptic terminals, thereby increasing the concentration of the transmitter in the synaptic cleft, which in turn leads to a decrease in the synthesis and turnover of serotonin (Stark R., et al., 1985).

The selective, but nonspecific for a certain receptor subtype (Stahl S., 1993) action of SSRIs does not always increase the effectiveness of treatment, especially when it comes to the treatment of patients suffering from severe depression (Anderson I., Tomenson B., 1994; Burce M., Prescorn S., 1995).

SSRI drugs have completely different chemical structures and differ from each other in pharmacokinetic parameters, dosages and side effect profiles. The selectivity of 5-HT reuptake inhibition reduces side effects, improves tolerability and reduces drug discontinuation compared with TCAs (Anderson I., Tomenson T., 1994).

Table Comparative characteristics of SSRIs according to the intensity of the antidepressant effect

Note: +++—significant intensity, ++—moderate intensity, +—weak intensity of the effect.

It is necessary to emphasize the relative safety of SSRIs (fewer number and severity of side effects) and greater comfort of treatment (the possibility of carrying out therapy on an outpatient basis).

SSRIs are also characterized by low toxicity (the risk of death in case of poisoning or overdose is almost zero), as well as the possibility of using drugs in this group in patients with contraindications to the use of TCAs (heart rhythm disturbances, difficulty urinating due to prostatic hypertrophy, closed-angle glaucoma) ( Mashkovsky M.D., 1997).

It should be noted that the literature has reported cases of central and peripheral side effects during treatment with SSRIs (Baldessarini R., 1989).

These drugs are more expensive antidepressants than other drugs used to treat depression.

Most selective serotonin reuptake inhibitors (SSRIs) are long-acting and are used in fixed doses. The pharmacokinetics of various representatives of the SSRI group has its own characteristics depending on the age of the patients and somatic burden. Thus, the half-life of fluvoxamine increases slightly in elderly patients and patients with liver pathology (Raghoebar M., Roseboom H., 1988). The half-life of sertraline is also influenced by age (Warrington S.1988), and the effect of fluoxetine is quite significantly affected by the functional capabilities of the liver (Bergstrom M., Lemberg L, et al., 1988).

Clinical trials of SSRIs have demonstrated that they, like TCAs, are an effective treatment for most depressive conditions, including anxiety, sleep disturbances, psychomotor agitation and retardation. (Levine S. et al., 1987, Dunlop S. et al., 1990, Claghorn J., 1992, Kiev A., 1992).

Table Comparative assessment of the additional therapeutic effect of SSRIs

Indications for the use of SSRIs are severe and moderately severe depression (such as simple) with mild anxiety and restlessness (Pujynski S., et al., 1994; Pujynski S., 1996). In addition, SSRIs can be used to treat personality disorders, including anger reactions and impulsivity.

The medical literature emphasizes the sensitivity of vital disturbances to the action of these antidepressants (Laakmann G. et al. 1988).

A number of studies have described that patients in whom melancholy predominated in the structure of the syndrome demonstrated a good therapeutic response when using SSRIs (Reimherr F. et al., 1990, Tignol G. et al., 1992; Mosolov S.N., Kalinin V. .V., 1994).

Considering the good tolerability of these drugs, they are recommended for use in old age.

At the same time, most researchers note a fairly high anxiolytic activity of SSRIs (Amin M. et al., 1989; Kiev A., 1992, Bovin R.Ya., et al. 1995, Ivanov M.V. et al. 1995). At the initial stages of the emergence of SSRIs in the domestic literature, there were indications of low effectiveness, and sometimes even increased anxiety when using SSRIs in patients with anxious depression (Kalinin V.V., Kostyukova E.G., 1994, Lopukhov I.G. et al. , 1994, Mosolov S.N., et al., 1994).

In recent years, studies have been conducted comparing SSRIs with TCAs. Most authors note that the activity of new compounds is comparable to traditional drugs (Guelri J. et al., 1983; Shaw D. et al., 1986; Hale A. et al., 1991, Fontaine R. et al., 1991 ). When comparing SSRIs with TCAs, traditionally used in the treatment of anxiety and depressive conditions, it is usually indicated that the differences in the effectiveness of the studied drugs in their ability to relieve anxiety are not statistically significant (Feighner J., 1985, Laws D. et al., 1990 , Avrutsky G.Ya., Mosolov S.N., 1991, Doogan D., Gailard V., 1992).

According to many authors, SSRIs are effective in some cases when the use of TCAs turned out to be ineffective (Weilburg JB et al., 1989, Beasley CM et al. 1990; Ivanov M.V. et al., 1991; Bovin R.Ya. et al. al., 1992; Serebryakova T.V., 1994; Bovin R.Ya., et al. 1995). According to Beasley C., Sayler M. (1990), patients resistant to TCAs are sensitive to new drugs in 50-60% of cases.

It is necessary to emphasize the greater safety of SSRIs compared to TCAs (fewer number and severity of side effects), greater comfort of treatment (the possibility of carrying out therapy on an outpatient basis) (Boyer W. Feighner J., 1996).

When taking TCAs, 30% of patients are forced to abandon treatment due to the severity of side effects, while when new drugs are prescribed, only 15% of patients have to interrupt their medication (Cooper G., 1988).

S. Montgomery, S. Kasper (1995) showed that the frequency of drug discontinuation due to side effects was 14% of patients treated with SSRIs and 19% with TCAs. The advantage of second-generation antidepressants is especially important during long-term therapy (Medavar T. et al., 1987).

R.Ya. Bovin (1989) points to an increased risk of suicide in the early stages of TCA therapy. While in most studies on SSRIs, the authors pay attention to the high anti-suicide nature of these drugs (Fava M. et al., 1991; Cohn D. et al., 1990; Sacchetti E. et al., 1991) .

In addition to the treatment of depression, attempts are increasingly being made to long-term use of antidepressants (fluoxetine, sertraline) to prevent its relapse.

Cohn GN et al., (1990), given the good tolerability of SA, recommend their use in gerontopsychiatry.

There is no consensus regarding the speed of onset of effect when using SSRIs. According to foreign authors, the clinical effect of SSRIs is detected later than TCAs (Roose S, et al. 1994). At the same time, domestic scientists indicate that SSRIs tend to have a faster onset of therapeutic effect compared to other antidepressants (Avrutsky G.Ya., Mosolov S.N., 1991).

In the SSRI group, various drugs differ in the strength of their action on receptors and the level of selectivity. Moreover, selectivity and potency do not coincide. Paroxetine was found to be a more potent inhibitor of serotonin relapse, while citalopram was more selective. Differences in the selectivity and power of action on receptors determine not only the characteristics of the therapeutic effect of a particular drug, but also the presence of side effects (Thopas D., et al., 1987; Hyttel G., 1993).

Other things being equal, relapses of depression are more likely to occur after treatment with fluoxetine than with paroxetine and after treatment with citalopram than with sertraline; with an almost equal number of relapses during treatment with sertraline and paroxetine.

Since fluvoxamine and paroxetine have a pronounced sedative and anti-anxiety effect, their spectrum of activity is similar to drugs such as amitriptyline or doxepin. Most other drugs, especially fluoxetine, more closely resemble the profile of imipramine, as they have a disinhibitory effect and can increase symptoms of anxiety and restlessness (Caley Ch., 1993; Pujynski S., et al., 1994; Montgomery S., Johnson F., 1995 ). In the domestic literature there are also indications of low effectiveness, and sometimes even increased anxiety when using SSRIs in patients with anxious depression (Kalinin V.V., Kostyukova E.G., 1994, Lopukhov I.G. et al., 1994, Mosolov S.N. et al., 1994).

Due to the disinhibiting effect, such drugs should not be used for anxiety, restlessness, motor disinhibition, insomnia, suicidal thoughts and tendencies. According to S. Pujynski (1996), psychotic forms of depression are a relative contraindication to the use of SSRIs. However, Feighner J., Bouer W (1988), on the contrary, note the positive effect of these drugs even in the psychotic version of depression.

The most common side effects when taking serotonin inhibitors are gastrointestinal disorders: nausea and vomiting, constipation and loose stools. A number of patients experience weight loss.

Table Comparative characteristics of SSRIs by severity of side effects

Note: +++ - significant severity of side effects, ++ - moderate severity of side effects, + - mild severity of side effects

The next most common side effects are: restlessness, anxiety, insomnia, and less commonly, increased drowsiness.

Patients are especially concerned about sexual disorders that may occur when using these drugs. The most common of them: decreased libido, weak erection and difficulty achieving orgasm. In case of severe sexual disorders that have developed during SSRI therapy, the dosage of drugs is usually reduced or discontinued for several days. In some cases, drugs that are serotonin antagonists (cyproheptadine) or drugs that enhance sexual function (yohimbine) are prescribed.

The most frequently mentioned contraindications to taking SSRIs include: hypersensitivity to the drug, pregnancy (cases of treatment of depression during this period with fluoxetine are known) and breastfeeding (the effect of SSRIs on the fetus and child development has been poorly studied), epilepsy, impaired renal and liver function. Drugs in this group cannot be used for poisoning with alcohol and psychotropic drugs. SSRIs should not be used earlier than 2 weeks after the end of therapy with non-selective MAO inhibitors, as well as together with other drugs with serotonergic action (Feihner J., Boyer W., 1996).

All registered SSRIs can provoke a phase change from depressive to manic in individuals with bipolar disease, but such a phase change occurs less frequently than with the use of TCAs (Kharkevich M.Yu., 1996). In addition, when treated with antidepressants for dysthymia, 10% of patients experience mild mania.

Due to the trend towards wider use of serotonin reuptake inhibitors in the treatment of depression, it makes sense to dwell on the characteristics of individual representatives of this group of drugs.

In his practical work, a psychiatrist in a number of cases encounters difficulties in distinguishing the clinical manifestations of depression from the side effects of SSRIs, SSRI withdrawal syndrome, as well as potentially life-threatening serotonin syndrome.

In the practice of a psychiatrist, differential diagnosis of the withdrawal syndrome of these drugs, their side effects and serotonin syndrome with clinical symptoms of depression is of particular importance in the process of SSRI therapy. SSRI withdrawal syndrome, which occurs in the event of a rapid reduction in the dose of the drug or its abrupt withdrawal, is characterized by symptoms such as dizziness, nausea, anxiety and headache. As noted above, side effects of SSRIs usually appear in the first two weeks of therapy and include asthenia, diarrhea, nausea, anxiety, dizziness, sleep disturbance, nervousness and tremor. For serotonin syndrome, which occurs with an overdose of an SSRI or its combination with a TCA, abdominal cramps, psychomotor agitation, diarrhea, convulsions, tachycardia, hypo or hypertension, sweating, and hyperthermia are typical. In depression, the core of the depressive state is anhedonia.

Fluoxetine

One of the first serotonin reuptake inhibitors was fluoxetine (Prozac), which has been actively used since the early 80s to treat various depressive spectrum disorders. In addition, its positive effect in the treatment of bulimia was noted.

Fluoxetine is prescribed at a dose of 20 mg. once a day in the morning, if necessary, increase the dose to 40-80 mg. (in addition to tablet forms, a special solution of fluosetine 4 mg/ml is used abroad).

The drug is well absorbed when administered orally and is demethylated in the liver to form inactive metabolites and pharmacologically active norfluoxetine. Due to the peculiarities of metabolism, the effect of fluoxetine is quite significantly reflected in the functional capabilities of the liver (Bergstrom M., Lemberg L, et al., 1988). It suppresses the activity of hepatic cytochromes P4502D6, and therefore slows down the metabolism of a number of psychotropic drugs, including TCAs, with an increase in their concentration in plasma, which determines the possibility of toxic effects (Creve N., et.al., 1992).

The maximum concentration in the blood when taking fluoxetine is achieved after 6 hours. It has the longest half-life of all SSRIs, which in this case is two to three days, and the half-life of its active metabolite, norfluoxetine, reaches 7-9 days. This circumstance provides an advantage in the treatment of patients who may occasionally forget to take the next dose, but, on the other hand, it complicates the replacement of the drug with other antidepressants (especially MAOIs). It takes several weeks to achieve a stable concentration of the active substance. It was noted that, despite the anxiolytic effect, fluoxetine can increase the manifestations of anxiety and agitation at the initial stage of therapy.

In terms of its spectrum of action, fluoxetine is more reminiscent of the profile of imipramine, since it has a disinhibitory effect and can, as noted above, increase the manifestations of anxiety and restlessness (Caley Ch., 1993; Pujynski S., et al., 1994; Montgomery S., Johnson F., 1995). There is a point of view according to which, due to the disinhibitory effect, fluoxetine should not be used for anxiety, restlessness, motor disinhibition, insomnia, suicidal thoughts and tendencies, however, recent studies have shown that taking fluoxetine does not increase the risk of suicide (Freemante N., et.al ., 2000).

Fluoxetine (Prozac), compared to other SSRIs, eliminates signs of depression much more slowly (within 2-3 weeks), however, its final effect turned out to be similar to the effect of other drugs of this class (Edwards J., Anderson I., 1999). There are observations that fluoxetine is approximately equal to TCAs in its effectiveness in relieving symptoms of depression (Beasley C., et al., 1991).

At the same time, there is a point of view according to which fluoxetine is inferior to other SSRIs in its ability to relieve general manifestations of depression (Williams J., et al., 2000).

In the first days of using fluoxetine, and possibly also at further stages of treatment, nausea, akathisia, headaches, impaired visual acuity, and allergic skin reactions may be observed. Sexual dysfunctions have been reported when taking fluosetine (Guthrie S., 1991; De Vane C. 1994; Pujynski S., 1996).

Psychiatry Psychiatry and psychopharmacotherapy named after. P.B. Gannushkina No. 01 2004

D

All of the publications reviewed reflect significant changes in our ideas about selective serotonin reuptake inhibitors (SSRIs) - antidepressants that have both general properties and individual characteristics of pharmacological activity. Therefore, it is advisable to preface the analysis of these studies with a brief summary of the current understanding of the problem of SSRIs. The mechanism of the antidepressant action of SSRIs—inhibition of serotonin reuptake (reuptake), leading to an increase in the amount of serotonin—is in good agreement with the basic principles of the classical monoamine theory of depression. Indeed, a deficiency of the neurotransmitter serotonin in serotonergic synapses, which underlies the development of depression, can be eliminated with the help of SSRI antidepressants. Since neurotransmitter deficiency in serotonergic synapses underlies not only depression, but also anxiety disorders and behavioral disorders, the SSRI group is used to treat not only depressive disorders, but also panic disorder, obsessive-compulsive disorder and a number of other mental disorders (aggression, impulsive behavior). behavior, etc.). An increase in the amount of serotonin, however, leads not only to the development of the therapeutic effects of SSRIs, but also to the appearance of side effects (anxiety, nausea, some sexual disorders, etc.). At the same time, side “serotonin” effects often precede the development of the therapeutic effect, but as treatment continues, they do not increase, but, on the contrary, are reduced or disappear completely. This sequence of development of the effects of SSRIs is probably explained by the pharmacodynamic features of their action, which occurs in several successive stages. Thus, the main, or “primary,” serotonergic action underlies both the therapeutic effect of SSRIs and a number of common side effects. As data accumulated on the mechanisms of action and clinical effects of SSRIs, it became obvious that in addition to inhibiting the serotonin reuptake, they also have other, so-called secondary pharmacological properties. It turned out that SSRIs can also inhibit the reuptake of norepinephrine and dopamine, have a direct stimulating effect on serotonin 2C receptors (ST2C), inhibit muscarinic cholinergic receptors (MCRs), interact with sigma receptors, inhibit nitroxide synthetase (NOS), and also inhibit a number of isoenzymes cytochrome P-450 (1A2, 2D6, 3A4), which are involved in drug metabolism (Stahl, 2000a). Moreover, each SSRI has its own individual set of these secondary pharmacological properties. For example, fluoxetine, in addition to inhibiting the serotonin reuptake (main effect), also inhibits the norepinephrine reuptake, directly stimulates CT2C, and inhibits isoenzymes 2D6, 3A4 from the cytochrome P-450 family (CTX P-450). Secondary pharmacological properties of paroxetine are manifested in the form of inhibition of norepinephrine retake, inhibition of MChR (anticholinergic effect), inhibition of NOS, as well as inhibition of CTX P-450 2D6. Only citalopram has practically no secondary pharmacological properties, which allows us to consider it the most typical representative of the SSRI group. It is the secondary pharmacological properties, according to some leading researchers (Stahl, 1998, 2000a; Goodnick and Goldstein, 1998), that distinguish one SSRI from another and explain why in some patients one SSRI is more effective than another and/or better tolerated. Let us illustrate this point with several examples. The presence of anticholinergic action in paroxetine leads to the fact that when taken, a rapid reduction of anxiety and insomnia occurs, while the initial activating effect characteristic of the SSRI group is less pronounced, and side effects such as vomiting or diarrhea are less pronounced. Accordingly, the antidepressant in question may be preferable in the treatment of anxiety-phobic disorders, anxious depression, as well as depressive conditions that occur with appetite disturbances. On the contrary, the drug will be less well tolerated if ideational and motor inhibition is expressed in the structure of the affective (depressive) disorder. In addition, the anticholinergic properties of antidepressants are potentially associated with the development of constipation, weight gain, dry mouth, urinary retention, sexual dysfunction and withdrawal symptoms. The presented considerations are in good agreement with clinical observations. Indeed, paroxetine is widely used as monotherapy for anxiety-phobic disorders (Schatzberg, 2000). However, paroxetine is associated with greater (compared with sertraline) weight gain (Aberg-Wistedt, 2000), more frequent (compared with fluoxetine) constipation (Geretsegger et al., 1994) and more severe symptoms (compared with fluoxetine). other SSRIs) withdrawal reactions (Hindmarch et al., 2000). Although all SSRIs are capable of causing reversible disorders of sexual function (decreased libido, anorgasmia, impotence, delayed ejaculation), it is paroxetine that causes these effects more often than other thymoleptics in this group (Montejo-Gonzales et al., 1997; Waldinger et al., 1998). If paroxetine has an additional moderate “sedative” effect, then when taking fluoxetine, which has the property of directly stimulating CT2C receptors, the initial activating effect of SSRIs is enhanced. In this case, increased anxiety, sleep disturbance, suppression of appetite and weight loss are possible. It is very likely that this antidepressant will be preferable in the treatment of depression that occurs with motor retardation and hypersomnia, and it may also be more effective than other SSRIs for bulimia and binge eating. At the same time, fluoxetine may be poorly tolerated by patients with psychomotor agitation, anxiety and insomnia. Clinical observations confirm the validity of this kind of assumption. Fluoxetine has demonstrated superior efficacy over other SSRIs in the treatment of bulimia nervosa (Fuller et al., 1991; Goldstein et al., 1994). Some studies suggest that patients taking fluoxetine do not experience weight gain (Reimherr et al., 1998) or even decrease (Harto et al., 1988). On the other hand, in the treatment of depressive conditions, fluoxetine is more likely than another SSRI, sertraline, to cause increased anxiety and insomnia (Aguglia et al., 1993). Unlike other SSRIs, citalopram does not have pronounced secondary pharmacological properties that would lead to a shift in the spectrum of its effects towards sedation or activation. Side effects of the drug are more predictable, since they are caused only by serotonergic mechanisms common to SSRIs. Accordingly, it becomes possible to prescribe an antidepressant in situations that place increased demands on safety and tolerability, as well as to achieve greater compliance (patients’ agreement with the treatment), especially at the beginning of therapy, which in some cases can contribute to a more rapid development of the therapeutic effect. The above considerations are fully consistent with clinical observations. Thus, it has been shown that citalopram has a favorable tolerability profile in elderly patients (Hakkarainen, Tanghoj, 1998), children and adolescents (Thomsen, 1997), and general practitioners (Wade, Rosenberg, 2001). The antidepressant does not cause changes in body weight (Wade et al., 1999) and, compared with sertraline, is associated with greater compliance and rapid onset of therapeutic effect (Stahl, 2000). Let us now consider, in the light of the presented data, the materials of studies related to the transfer of patients taking fluoxetine and paroxetine to treatment with citalopram. In the first of these works, the study material consisted of depressed patients who were treated with fluoxetine, but without effect (nonresponders). Unfortunately, the publication does not provide data on the syndromic features of the depressive states that these patients had. Considering the secondary pharmacological properties of fluoxetine mentioned earlier, it can be assumed that its low effectiveness in these specific cases could be associated with the presence of severe anxiety disorders in the clinical picture of depression. A number of indirect signs also indicate this. If this assumption is correct, then it is clear why the subsequent use of citalopram, which lacks a pronounced activating effect, led to high compliance, a significant reduction in depressive disorders and a small number of observed side effects. The second study included patients with intolerable side effects resulting from paroxetine use. Most of these effects are associated with the secondary pharmacological properties of the drug. Obviously, the prescription in these conditions of another SSRI - citalopram, which does not have the “additional” side effects characteristic of paroxetine, could not but lead to a decrease in the number of adverse events, an increase in compliance, an improvement in the quality of life of patients and a reduction in depressive disorders themselves. The correct position of the authors of publications deserves special consideration. Both publications emphasize that the results of the studies in no way mean that one antidepressant (cipramil) is generally more effective than another (fluoxetine) or better tolerated than a third (paroxetine). It is repeatedly noted that the data obtained only indicate that: 1) in cases of insufficient effectiveness of fluoxetine, switching to citalopram can lead to significant improvement in most patients and 2) in case of intolerance to paroxetine, switching to citalopram in most patients will lead to a reduction in side effects, improvement compliance and reduction of depressive disorders. The authors do not hide their pragmatic approach; they just need to empirically prove the feasibility of transferring patients from one specific SSRI to another specific representative of this group of antidepressants in cases where it is necessary to change therapy due to insufficient effectiveness or intolerance of the drug. This practical purpose may also explain the relative simplicity of the study design. At the same time, the authors have no doubt that such “transitions” are possible in relation to other SSRIs. By the way, one of the first works in this area concerned the transfer of patients with intolerance to fluoxetine to sertraline (Brown, Harrison, 1995). It is difficult to dispute another conclusion contained in both publications: in order, if necessary, to reasonably replace one SSRI with another, it is necessary to conduct appropriate research and prove the feasibility of such a replacement. The same applies to the transfer of patients with SSRIs to drugs of other pharmacological groups, for example, to thymoleptics of the so-called double action. PS Already at the time of writing these comments, an article was published in the May issue of the Journal of Clinical Psychiatry (J Clin Psychiatry 2003; 64 (5, May): 562–7) about the successful transfer of depressed patients with fluoxetine intolerance to citalopram. Thus, in practice, the proposal is put into practice regarding the need for empirical evidence of each specific replacement of one antidepressant with another.

Fluvoxamine

Fluvoxamine (fevarin), as a selective serotonin reuptake inhibitor, has a distinctly activating, mood-enhancing effect, it calms, stabilizes the activity of the autonomic system and can be recommended for a combination of depression and anxiety. In addition, the positive aspect of fluvoxamine treatment is its relatively rapid onset and smooth action, which, as a rule, contributes to the establishment of a good relationship between the patient and his attending physician.

Fluvoxamine is prescribed in a dose of 50 mg. per day once in the evening. The dose of the drug can be increased to 100 mg. (average dose of effectiveness) for 5-7 days. If necessary, the dosage of the drug can be further increased at intervals of 2-4 weeks (maximum daily dosage - 500 mg), starting with a dose of 150 mg. the drug is prescribed several times a day.

The active metabolites of fluvoxamine are unknown. The average half-life is 20 hours, plasma concentrations are not proportional to the dose taken

In most cases, symptoms of an anxiety disorder are eliminated earlier than those of a depressive disorder. This was clinically manifested by an improvement in the general condition of the patients, leading them to greater composure, confidence and external calm. The effectiveness of this drug is noted in patients with obsessive disorders and social phobia, in particular in childhood.

Adding fluvoxamine to atypical neuroleptics can reduce the severity of primary negative symptoms in patients with chronic schizophrenia. At the same time, comparative studies have shown that among the group of selective serotonin reuptake inhibitors, it has the greatest number of side effects (Freemante N., et al., 2000), sertraline has the least (Edwards J., Anderson I., 1999 ).

Publications in the media

Depressive disorders are persistent, relapsing diseases that cause suffering both to the patients themselves and to their family members. The lifetime risk of developing depression ranges from 10 to 25% in women and from 5 to 12% in men. Depression can occur at any age, in people of any race and socioeconomic status. The era of psychopharmacology of depression began in the 1950s with the discovery of the thymoanaleptic effect of imipramine and the development of a whole group of drugs with thymoanaleptic action - tricyclic antidepressants. At the same time, another class of antidepressants with a special mechanism of action, designated “monoamine oxidase inhibition” (MAOI), was created.

CHAKHAVA Konstantin Otarovich, Ph.D. honey. Sciences, Art. scientific employee of the department of new means and methods of therapy, department of border psychiatry, Federal State Institution “State Scientific Center for Social and Forensic Psychiatry named after. V.P. Serbian Federal Agency for Health and Social Development"

Tricyclic antidepressants (TCAs) are still considered the “gold standard” of psychopharmacotherapy, but a large number of side effects significantly limit their use. Poor tolerability of TCAs leads to a decrease in the quality of life of patients due to the so-called. behavioral toxicity, which often prompts the doctor to reduce the dosage of prescribed antidepressants and use drugs of this group in insufficient subtherapeutic doses. The use of MAOIs is also accompanied by a large number of side effects, primarily due to the incompatibility of these drugs with a number of foods.

The use of TCAs and MAOIs in recent decades has become increasingly limited not only due to the high risk of side effects, but also due to the potential danger to life in case of overdose and interaction with a number of somatotropic drugs in the general therapy clinic (depression in patients after myocardial infarction , unstable angina, cardiac rhythm and conduction disturbances, gastric ulcer, cancer, etc.). The synthesis in 1988 of the first drug from the group of selective serotonin reuptake inhibitors (SSRIs), fluoxetine, marked a new stage in the psychopharmacotherapy of depression. This drug had a significantly better tolerability and safety profile compared to TCAs and MAOI class antidepressants. The therapeutic effect of SSRIs is associated with inhibition of the reverse penetration of serotonin from the synaptic cleft into the presynaptic neuron. The drugs selectively act on one subtype of serotonin receptors – 5HT-1. SSRIs are widely used in the treatment of endogenous, nosogenic (somatogenic and psychogenic) depression, dysthymia, and depressive disorders with organic brain lesions. Along with this, drugs in this group (to varying degrees each) show quite high effectiveness in the treatment of anxiety-phobic disorders - generalized stress disorder, panic attacks, social phobia, post-traumatic stress disorder, as well as eating disorders and obsessive-compulsive disorder. SSRIs have virtually no effect on the adrenergic and cholinergic systems. Side effects with SSRI therapy are relatively rare. However, the side effects of these drugs should not be underestimated. Among the undesirable effects of therapy, the most commonly observed disorders are gastrointestinal disorders, loss of appetite, nausea, and less commonly, vomiting, diarrhea, and constipation. The introduction of modern generation antidepressants into clinical practice has ensured significant progress in the treatment of depression. One of the steps in this direction was the creation of citalopram. Citalopram, a bicyclic phthalan derivative, is considered in a number of studies as the standard of selectivity for SSRIs. This characteristic correlates with the virtual absence of influence of the drug and its metabolites on the noradrenergic and dopaminergic neurotransmitter systems, as well as with minimal affinity for receptor and enzyme systems (alpha and beta adrenergic receptors, histamine-1 receptors, D1 and D2 receptors, 5-HT1A, 5-HT1B and 5-HT2 receptors, benzodiazepine and opioid receptors). Unlike other representatives of this group of antidepressants (fluvoxamine, fluoxetine, paroxetine), the drug and its metabolites have practically no “secondary” pharmacological properties, i.e. do not bind to a large number of other receptors and enzymes (cytochromes P1A2, P2C19 and P3A4, P2D6, M-cholinergic receptors, nitroxide synthetase), which can make a positive contribution to the overall clinical effect. The systemic bioavailability of citalopram is close to absolute and amounts to 80%. Being a fat-soluble compound, citalopram easily (without connection with food intake) and quickly (after 2 - 4 hours) reaches its maximum concentration in biological fluids, and its lipotropic nature provides the active substance with easy penetration through the blood-brain barrier. Renal clearance during citalopram therapy remains within 20-25% due to alternative routes of final elimination, which, unlike other SSRIs, does not require dose adjustment even in cases of moderate renal failure. Having a higher selectivity compared to other SSRIs, the drug retains polyvalence and affects not only a wide range of disorders defined by pathologically reduced affect, but also other symptom complexes - anxiety, obsessive-phobic, behavioral, etc. A significant characteristic of the action of citalopram in outpatient and inpatient practice is the speed of manifestation of therapeutic activity. At the clinical level, the shortest latent period between the prescription of the drug and a noticeable thymoleptic effect is observed already in the first 7 to 10 days of therapy. A study of the effectiveness of citalopram in vascular, in particular multi-infarction, dementia and in Alzheimer's disease showed the possibility of reducing symptoms of emotional dullness (coarsening), depressive mood, increased excitability and restlessness, internal tension, a tendency to excessive anxiety in ordinary situations, the formation of fears and the formation of panic attacks, as well as asthenic symptoms and even confusion. The use of therapeutic doses of citalopram is not accompanied by cardiotoxic effects (changes in blood pressure, the appearance of arrhythmia or ECG abnormalities), regardless of the duration of treatment and the presence of cardiac pathology. The possibilities for treating depression in general medical practice are expanding due to the identification of citalopram (as well as other SSRIs) with a somatoregulatory effect. The peculiarity of this effect of citalopram is its antinociceptive effect in chronic pain disorders associated both with and independent of depressive affect. Along with a high therapeutic index (safety in case of overdose), citalopram is characterized by safety during long-term use, favorable pharmacological and pharmacokinetic interactions, and optimal tolerability. Citalopram does not contribute to changes in appetite and weight. Citalopram is easy to use: taken once a day at any time of the day, regardless of food intake. The initial and maintenance dose is 20 mg/day. Does not interact with alcohol. Thus, citalopram is the most selective serotonin reuptake inhibitor. It does not interact with other mediator systems and causes minimal side effects. Equally highly effective for depression of any etiology, severity and structure. Citalopram equally affects the entire spectrum of depressive states: anxious, apatho-adynamic, melancholy, etc. It has a minimum of interactions (drug interactions) with other drugs, incl. in the treatment of comorbid depression in somatic patients. Compatible with analgesics, antihistamines, antihypertensive drugs, incl. beta-blockers and other cardiotropic drugs. Does not cause drug dependence. With citalopram therapy, withdrawal syndrome is practically not recorded. It is well tolerated and safe for use in the elderly. Significantly reduces the frequency of recurrent depression with long-term use. The modern therapeutic approach is determined by the principle of effectiveness (general effectiveness, features of the spectrum of action, time of onset of clinical effect, preventive effectiveness) and the principle of safety of treatment. In this regard, citalopram has a number of advantages in comparison with other SSRIs and reference antidepressants.

Citalopram

Citalopram has a significantly higher level of selectivity for serotonin transporters compared to norepinephrine and dopamine transporters.

The drug is prescribed in a dose of 20 mg. per day once a day in the morning. For most patients, this dose is the most effective; the maximum daily dose of the drug is 60 mg.

Citalopram practically does not enter into drug interactions, due to the fact that it has little effect on the activity of some liver enzymes (cytochrome P450 enzyme system). Therefore, it is often used in the treatment of depressive conditions that develop as a result of chronic somatic diseases. Interdrug interactions of the drug are minimal. Under the influence of cytochrome P450, citalopram is converted into two main metabolites: demethylcitalopram and didemethylcitalopram. These metabolites have pharmacological activity, but much less than that of citalopram itself. The half-life of citalopram is 30 hours. It is characterized by a linear dependence of plasma concentrations depending on the dose in the therapeutic interval. For the treatment of severe depression, the dose of the drug should be increased.

The use of citalopram is recommended in general medical practice, in elderly patients and persons who have suffered a cerebral stroke.

When prescribing citalopram, the percentage of men with sexual dysfunction, a side effect that is relatively common when prescribing drugs in this group, turned out to be extremely small. Headache and nausea were the most common side effects of citalopram treatment during the first two weeks of treatment.

Antidepressants

Of all psychiatric disorders, depression is considered the most underestimated. 10–20% of all people experience this disease at least once in their lives. Among the elderly, the prevalence of depression increases and reaches 15–25%. The main problem of depression is the insufficient development of its diagnosis and the lack of psychiatrists. Therefore, at first we considered it unnecessary to immediately burden you with the classification of antidepressants, but to pay attention to the pathogenesis of this disease. It is knowledge of the theory that helps to understand why groups of pharmaceutical drugs such as sedatives and anxiolytics are not effective enough in monotherapy.

For a long time, electroconvulsive therapy was actively used in the treatment of depression, the purpose of which was to enhance the metabolism of neurotransmitters in the brain. Surprisingly, 75% of patients actually experienced improvement in symptoms. For example, the famous pianist Vladimir Horowitz suffered from depression for years, and it was electroshock therapy that helped him return to the stage.

Vladimir Horowitz

From 15 to 30% of all depressive disorders tend to be chronic and have multiple relapses. That is why most treatment regimens are designed for a long period of time. Since some depressive disorders are associated with other diseases, it is necessary to pay special attention to the possibility of combining different groups of pharmaceuticals.

There can be several causes of depression. This condition is characterized by a number of physiological changes: the concentration of norepinephrine in the body tissues decreases, the number of serotonin receptors decreases, and their affinity for ligands decreases (5-HT 2A, 1B, 1A in the cerebral cortex - if you are not sure you can easily say, which receptor is responsible for what, we recommend re-reading our article about serotonin - https://goo.gl/iiUYKk), the activity of corticotropin and glucocorticoids increases, atrophy of the frontal and prefrontal cortex of the hippocampus is observed, there is also a decrease in the number of connections between neurons in the frontal cortex the number of blood vessels decreases, the concentration of melatonin decreases, which leads to sleep disorders . It is worth noting that depressive disorders are often inherited (40–50% of unipolar and 60–70% of bipolar disorders). However, genetic penetrance, as in the case of other mental diseases, is reduced. Therefore, 90% of patients do not have similar cases of the disease in their family. Disorders intensify depending on the duration of the disease.

In 1965, the American doctor Schildkraut suggested that depression may be based on processes leading to a decrease in the concentration of serotonin and norepinephrine in the synaptic cleft. In humans, in the posterior raphe nucleus and locus coeruleus of each cerebral hemisphere there are up to 165,000 noradrenergic and 55,000 serotonergic neurons. That is why even a slight decrease in the number of these neurons can already cause characteristic symptoms. Also, with depression, the production of presynaptically located alpha-2-adrenergic receptors increases. When norepinephrine acts on autoreceptors and serotonin acts on heteroreceptors (neurotransmitters are released from the same neuron), the entire process slows down according to the principle of negative feedback, which only increases the lack of these neurotransmitters in the synaptic cleft. Lack of adrenaline, in turn, leads to apathy and a feeling of fatigue.

Serotonin is credited with participating in the formation of contacts between neurons. Many indicators related to serotonin metabolism, such as, for example, decreased concentrations of serotonin and its receptors, mutations in genes encoding serotonin transport systems, and decreased production of serotonin-binding proteins such as p11, correlate with the severity of depressive disorder. It is assumed that a decrease in dopamine concentration also affects the development of depression, but is not its root cause.

Also, depressive disorders are characterized by a decrease in neurogenesis , mainly due to stress-induced hypercortisolism and dysfunction of the neurotrophic factor BDNF (brain derived neurotrophic factor). As a result of experiments, it was proven that increasing the synthesis of BDNF helped overcome the symptoms of depression caused by a deficiency of this factor. Scientists were able to prove that the transcription repressor GATA1 is able to reduce the number of synapses in the prefrontal cortex of animals and thus provoke the development of depressive symptoms in them. As we already wrote in our infographics (https://goo.gl/611CMc), the development of this disease is influenced by disruption of the hypothalamic-pituitary axis , as well as an increase in neuronal cholinergic transmission. Many pharmacological drugs, in turn, can cause depressive disorders (glucocorticoids, very high or low concentrations of gestagens, antipsychotics, anticonvulsants, as well as antihypertensive drugs, fluoroquinolones and interferons). Characteristic symptoms are also caused by withdrawal from opioids and benzodiazepines after long-term use.

Having analyzed these mechanisms, we can finally move on to the main thing and answer the question - what properties should drugs of this group have?

All antidepressants, except lithium and agomelatine, lead to increased concentrations of norepinephrine and/or serotonin in the synaptic cleft. This can be done in several ways: blocking the transport systems that carry these mediators back into the neuron, reducing the activity of alpha-2 adrenergic receptors (as mentioned above), reducing the activity of the enzyme responsible for the breakdown of serotonin and norepinephrine (MAO A, MAO A/B ), and also act on the serotonin 5-HT 2C receptor.

Norepinephrine enters the presynaptic terminal using a special highly selective transporter NET and partially through microglial cells using less selective transport systems. A small amount of norepinephrine can diffuse into the intercellular space, and from there directly into the blood. With depression, the concentration of norepinephrine decreases. Antidepressant drugs are able to displace norepinephrine from its connection with the receptor, which increases its concentration in the synaptic cleft and interaction with receptors. On the part of the adrenergic system, a number of changes are also observed during antidepressant therapy: the production of postsynaptic alpha-1 and beta receptors increases and the number of presynaptic alpha-2 receptors decreases. However, these changes are not typical for therapy with all types of antidepressants.

Serotonin is sent back into neurons using the SERT protein, which, as you might guess, can also be blocked to increase the amount of serotonin in the synaptic cleft. The effect of antidepressants on this system is not the same, since all receptors are very different in their structure and location. However, it can be said that under the influence of antidepressants, in general, the production of postsynaptic 5-HT2A receptors decreases, which correlates with the anxiolytic effect of these drugs, the production of presynaptic 5-HT1A receptors decreases (they have inhibitory potential according to the principle of negative feedback), and 5-HT2C is also blocked receptors, which leads to an anxiolytic effect and increased release of norepinephrine and dopamine in the prefrothal cortex.

Direct antagonists of presynaptic alpha-2-adrenergic receptors mianserin and mirtazapine block the processes of autoinhibition of norepinephrine release, which also leads to an increase in norepinephrine in the synaptic cleft. The number of presynaptic alpha-2 receptors decreases, and postsynaptic alpha-2 receptors begin to bind adrenaline more strongly.

Antidepressants, except buspirone, do not directly affect dopamine metabolism, so they do not have antipsychotic potential (except that trimipramine can block the dopamine D2 receptor). But, nevertheless, dopamine transmission increases under the influence of antidepressants. This is due to the fact that the norepinephrine transport protein NET is also able to bind to dopamine. The D2 receptor agonist pramipexole is approved for use in depressive disorders in Parkinson's disease.

It is worth noting that many mechanisms of action of antidepressants remain unexplored. For example, it is impossible to predict its strength of action based on the chemical structure of a particular antidepressant. The therapeutic effect of the drug hardly correlates with the strength of the blockade of the serotonin and norepinephrine transporter proteins. It was also not possible to note the relationship between the number of monoamine receptors and the severity of the clinical effects of antidepressants.

Side effects are mainly particularly pronounced in two groups of antidepressants - alpha-2-adrenergic receptor antagonists and tricyclic antidepressants. These two groups of drugs act not only on those receptors that were described in the previous post, but also on muscarinic, alpha-1-adrenergic and histamine receptors. It is because of their effect on these systems that many patients refuse to take medications from these groups, preferring selective serotonin and/or norepinephrine reuptake inhibitors.

Tricyclic antidepressants (eg, amitriptyline) and alpha-2 adrenergic receptor antagonists have a fairly high affinity for muscarinic acetylcholine receptors. By blocking them, these substances cause side effects similar to those of atropine: dry mouth (risk of developing caries when consuming chewing gum containing sugar), mydriasis and impaired eye accommodation (and, as a result, an increased risk of falls), increased intraocular pressure, constipation , impaired urination, confusion up to anticholinergic delirium with optical hallucinations, tachycardia (intensified by blockade of alpha-1-adrenergic receptors). In older people, taking drugs that cause xerostomia is especially problematic. They have to constantly drink water, increasingly replacing it with drinks high in sugar, which affects the metabolism of carbohydrates, leading to the development of tooth decay and weight gain. Dry mouth is a side effect of more than 500 medications, including mainly anticholinergics (tricyclic antidepressants, antipsychotics, histamine receptor antagonists type 1), as well as antihypertensive drugs (beta blockers and calcium channel inhibitors). By following the rules of oral hygiene and the recommendations of the dentist, you can successfully avoid this side effect. As you can guess, it is better not to combine drugs from these groups with other substances that cause atropine-like effects (neuroleptics, antiparkinsonian drugs, type 1 histamine receptor blockers).

Blockade of adrenergic alpha-1 receptors by tri- and tetracyclic antidepressants leads to vasodilation, which increases the risk of hypotension. Therefore, these groups of medications are not recommended to be taken at night. In case of heart failure and severe hypertension, orthostatic hypotension caused by antidepressants can be especially acute (in this case, therapy with sympathomimetics etilephrine and midodrine is recommended). There is also a risk of developing reflex tachycardia and rhythm disturbances, which can increase due to the simultaneous blockade of acetylcholine receptors and the resulting decrease in parasympathetic activity.

Tricyclic antidepressants and alpha-2 adrenergic receptor antagonists are capable of blocking type 1 histamine receptors almost as strongly as selective blockers of this group. This is due to the affinity of the domains that bind to these receptors: many substances that are antagonists of type 1 histamine receptors are also antagonists of the muscarinic acetylcholine receptor (this affinity is stronger than for the type 2 histamine receptor).

The main consequences of histamine type 1 receptor blockade are sedation and drowsiness. The sedative effect is sometimes considered not a side effect, but rather a desirable one, because patients often suffer from anxiety and insomnia, especially at the beginning of therapy. Negative effects, of course, will be disturbances in concentration and attention, which is very important if the patient needs to drive a vehicle.

Even the average person knows from the media another side effect of antidepressants - increased appetite and a tendency to gain weight. The fact is that type 1 histamine receptors are also located in the hypothalamus and are responsible for appetite. Signals from these receptors control satiety to the same extent as leptin. When they are blocked, accordingly, this signal weakens, which leads to the patient gaining weight. When blocking 5-HT2A receptors, this effect is especially pronounced. Sometimes patients gain 10 to 20 kilograms in weight, which, of course, affects self-esteem and thus the effectiveness of the therapy itself.

The purpose of taking antidepressants is to enhance the influence of norepinephrine, adrenaline and serotonin, which does not come without its side effects. Patients are prone to increased sweating, which is exacerbated by taking estrogens and the serotonergic opioid tramadol.

Norepinephrine increases the tone of the bladder sphincter, which leads to difficulty urinating. Serotonin causes nausea and diarrhea. Due to inappropriately strong release of antidiuretic hormone, hyponatremia (Parhon's syndrome) may develop when taking some antidepressants.

The use of antidepressants (in high concentrations) can lead to increased blood pressure. Also, when taking them, the development of anemia and agranulocytosis is possible. Some drugs, such as venlafaxine and mirtazapine, cause hair loss. There is a relationship between taking antidepressants and the development of restless legs syndrome.

Tri- and tetracyclic antidepressants

Drugs in this group are non-selective monoamine reuptake inhibitors. This complex name hides the very mechanism of action of these antidepressants.

This group of antidepressants is the only one that received its name due to the structure of the molecule. In 1957, the form of the tricyclic antipsychotic drug chlorpromazine was deciphered. This similarity in the structures of neuroleptics such as phenothiazine and thioxanthene explains the similarity of the effects of antidepressants and neuroleptics, such as trimipramine, which also has an antipsychotic effect.

Let us recall that drugs in this group inhibit the reuptake of norepinephrine and serotonin by neurons (with the uptake of the former predominant), inhibit the 5-HT-2A/C serotonin receptor (anxiolytic effect of clomipramine), and also block the histamine receptor type 1 (sedative effect). In small quantities, they also inhibit dopamine reuptake.

Tricyclic antidepressants have lipophilic properties, which allows them to easily cross the BBB. In their metabolism, a special role is played by the so-called first pass effect, which determines their low bioavailability. TCAs are metabolized in the liver, so if they are overdosed, forced diuresis does not bring results. Under the influence of CYP2D6, tertiary amines (amitriptyline, imipramine) are converted into secondary amines (desipramine, nortriptyline).

Depending on the type of parent compound, all TCAs are divided into three groups:

Imipramine type: imipramine and clomipramine. Amitriptyline type: amitriptyline, amitriptyline oxide, doxepin, opipramol, trimipramine. Desipramine type: desipramine, nortriptyline.

The effect of TCAs is not immediately noticeable. In the first week, the sedative component mainly predominates, in the second - the thimeric component, in the third week their thymoleptic effect is observed. This inhibition of the effects of TCAs makes it possible to assume that not all the mechanisms of action of these drugs have been studied, because the concentration of neurotransmitters in the synaptic cleft increases already on the first day of administration.

Amitriptyline is used for severe forms of depression. In low dosages (25–50 mg), amitriptyline is also used as a coanalgesic for neuropathic pain. Like many other drugs in this group, amitriptyline has a wide range of side effects (see part 2), which, however, weaken over time. Tricyclic antidepressants also inhibit adrenergic α1 receptors, muscarinic acetylcholine receptors and type 1 histamine receptors. Anticholinergic effects include dry mouth, diuresis disturbances, constipation, accommodation disturbances, visual disturbances, increased intraocular pressure, tachycardia and delirium (especially in elderly patients. TCAs are contraindicated in dementia). The development of seizures of central origin is possible. TCAs have cardiotoxic and negative inotropic effects, which lead to hypotension, an increase in the QRS complex and the development of cardiac arrhythmias. Due to the blockade of adrenergic α1 receptors, the development of orthostatic hypotension is observed. Due to the blockade of type 1 histamine receptors, patients experience dizziness, fatigue, weight gain and appetite. This is why taking TCAs is recommended before bed. TCAs also provoke the development of Parhon syndrome. Symptoms of TCA overdose are similar to those of serotonin syndrome: fever, extrasystole, tachycardia, confusion, mydriasis, hallucinations, visual impairment. It is recommended to treat this condition with physostigmine, as well as activated carbon, anticonvulsant drugs, sodium bicarbonate and infusion of isotonic solutions.

Nortriptyline is a metabolite of amitriptyline and is more suitable for combination therapy, primarily due to its weakened anticholinergic effect and cardiac side effects. However, desipramine-type drugs, which include nortriptyline, are characterized by a particularly pronounced thimeretic effect. Imipramine-type drugs are no different in this.

Imipramine is a highly potent norepinephrine transporter inhibitor. Because it only slightly inhibits type 1 antihistamine receptors, the sedative effect of imipramine is significantly reduced. Its anticholinergic side effects are much less pronounced. Trimipramine also inhibits the D2 receptor and is the only drug in this group that has an antipsychotic effect.

Clomipramine , on the contrary, differs in that it inhibits SERT quite strongly. Its associated anxiolytic effect is used in the treatment of obsessive-compulsive disorders.

Doxepin binds to H1 receptors, inhibiting them, which is used in the treatment of neurodermatitis (off label use), reducing the feeling of itching, and the sedative component helps to sleep. The drug is prescribed for alcohol withdrawal syndrome and opioid withdrawal.

Trimipramine , as noted earlier, is the only one of this group that has an antipsychotic effect, since it is an antagonist of dopamine D2 receptors.

Opipramol has the structure of a tricyclic antidepressant but is unable to inhibit either NET or SERT. Its main function is the blockade of type 1 histamine receptors, which causes a strong anxiolytic effect and promotes better sleep without causing dependence like benzodiazepines.

It is worth noting that sodium channel blockade (amitriptyline) promotes the development of heart rhythm disturbances with an increase in the QT interval (but provides an analgesic effect). Blockade of muscarinic acetylcholine receptors is fraught with the development of tachycardia and sympathomimetic effects: increased blood pressure and tremor.

An increase in norepinephrine tone contributes to the development of excited states of the central nervous system, up to a convulsive attack. Metabolism of tricyclic antidepressants in the liver entails an increase in the concentration of liver transaminases in the blood. It is logical to assume that drugs in this group are not prescribed to patients with epilepsy, cardiac arrhythmia in liver diseases, prostate hyperplasia and glaucoma.

TCAs are used mainly for endogenous depression, but at the moment, due to side effects, drugs in this group are more likely to be reserve drugs. Abrupt discontinuation of TCAs provokes the development of insomnia and flu-like symptoms, and there is a positive correlation of abrupt discontinuation of TCAs with the incidence of suicide.

Tetracyclic antidepressants are inhibitors of adrenergic α2 receptors. They are weak inhibitors of NET and SERT, and their ability to block type 1 histamine receptors is responsible for their sedative effect early in therapy. Therefore, these drugs have been used for agitated depression. Mianserin and maprotiline are derivatives of mirtazapine. S-(+)-enantiomers are able to block adrenergic α2 receptors and 5-HT2 receptors. R-(-)-enantiomers also inhibit 5-HT3 receptors. Mirtazapine does not block monoamine uptake. Due to its sedative effect in the absence of anticholinergic side effects and only minor emetic effects, mirtazapine is used in geriatrics mainly as a hypnotic that does not affect REM sleep. Mianserin can cause agranulocytosis and aplastic anemia, therefore, when using it, it is recommended to regularly do blood tests. Mirtazapine most often provokes restless leg syndrome and weight gain of up to 10 kg in just a few weeks. Like tricyclic antidepressants, tetracyclic antidepressants are contraindicated in epilepsy, renal failure and glaucoma.

Selective monoamine uptake inhibitors

Depending on which neurotransmitter is reuptaken, drugs in this group of drugs are divided into several types: SSRIs, SSRIs and SNRIs .

The side effects of these groups of drugs are significantly less than those of tricyclic antidepressants. Selective uptake inhibitors do not affect the activity of the cardiovascular system, and also do not have anticholinergic and proconvulsant effects. Severe side effects include serotonin syndrome (https://goo.gl/qWHHpM). Its symptoms are abdominal pain, fever, tachycardia with increased blood pressure, hyperreflexia and myoclonus. Possible death. The cause of the development of serotonin syndrome may be an overdose of drugs that enhance serotonergic effects, especially the combination of selective serotonin reuptake inhibitors with tramadol, triptans, moclobemide, MAO inhibitors and lithium preparations.

SSRI

Venlafaxine and duloxetine block the reuptake of both serotonin and norepinephrine, and both are substrates of CYP2D6.

Venlafaxine (dosage 75-300 mg per day, half-life - 5 hours, active metabolite - desmethylvenflaxine) is characterized by low bioavailability (less than 20%) when taken orally. At low dosages, it is able to inhibit the reuptake of serotonin, and at high doses, norepinephrine, which, however, does not in any way affect its antidepressant potential. Venlafaxine is also capable of partially inhibiting dopamine reuptake.

Duloxetine (dosage 30–90 mg per day) blocks the reuptake of both neurotransmitters equally. As you can already guess, acting only on the reuptake of neurotransmitters, selective inhibitors of this group do not have atropinergic and sedating effects, unlike tricyclic antidepressants. Sometimes patients begin to complain of difficulty urinating, sweating and impaired potency, but this rarely leads to refusal to take medications. These drugs are contraindicated for liver disease, severe hypertension, epilepsy and glaucoma.

SSRI

Selective norepinephrine inhibitors (reboxetine, dosage 8–12 mg per day, half-life 13 hours, active metabolite desetylreboxetine) increase the concentration of norepinephrine in the synaptic cleft. Due to the numerous side effects associated with the influence of norepinephrine, SNRIs are used only for severe depressive episodes. Reboxetine is metabolized by CYP3A4, which limits its use in combination with drugs that affect the functioning of this cytochrome.

SSRIs

With selective blockade of only serotonin reuptake, the antidepressant effect of this group is better expressed. Drugs in this group include citalopram (dosage 10-60 mg per day, half-life - 33 hours, active metabolite - desmethylcitalopram), its more SERT-specific S-enantiomer escitalopram (dosage 5-20 mg per day), sertraline (dosage 50 -200 mg per day, half-life 24 hours, active metabolite - desmethyl sertraline), paroxetine (dosage 20-60 mg per day, half-life 8-30 hours), fluoxetine (dosage 10-60 mg per day, half-life 48- 96 hours, active metabolite - norfluoxetine) and fluvoxamine (dosage 50-300 mg per day). The last two drugs can also act on opioid receptors, producing an analgesic effect. Otherwise, the antidepressant effect of the above drugs is approximately the same. Also, their concentration does not change significantly in renal failure. According to many meta-analyses, escitalopram and sertraline have a better antidepressant effect, and citalopram has fewer side effects with good effectiveness. Escitalopram, depending on the dosage, can prolong the QT interval, which, unfortunately, does not allow the drug to achieve a better effect due to the need to reduce the dosage. Differences in the use of individual representatives of this group are presented in the table attached to the post. Fluoxetine and paroxetine are strong and citalopram and escitalopram are weak inhibitors of CYP2D6. Blocking this system increases the concentration of tricyclic antidepressants and antipsychotics in the blood, and the effect of tamoxifen (an estrogen antagonist, used in the treatment of breast cancer), on the contrary, decreases, since tamoxifen, being a prodrug, is activated in this system in the liver.

Blocking SERT itself causes a number of side effects, such as drowsiness and akathisia (internal restlessness due to serotonin 5HT2 receptors), especially at the beginning of therapy. Serotonin is also involved in platelet aggregation processes. The platelet membrane contains exactly the same serotonin transporter SERT as in neurons, therefore, due to a lack of serotonin, its vasoconstrictor effect on 5-HT-2A serotonin receptors is reduced. Therefore, drugs in this group should be used with caution if the patient has chronic inflammatory bowel diseases or is taking salicylic acid drugs (antiplatelet agents) or vitamin K antagonists (indirect anticoagulants). Due to increased stimulation of serotonin 5HT-2A receptors in the very posterior field (area postrema) and 5HT-3 receptors in the gastrointestinal tract, these drugs provoke vomiting, which can be stopped with 5-HT3 serotonin receptor blockers (ondansetron). It is precisely because of the feeling of nausea that drugs in this group at the beginning of therapy lead to a decrease in the patient’s weight. Due to increased secretion of antidiuretic hormone, fluid retention occurs in the body, which leads to a decrease in sodium concentration in the blood in the first 4-6 weeks after starting medication in 10-20% of patients. Impaired potency is also observed when taking this group of antidepressants.

Sertraline reversibly reduces sperm quality and causes ejaculation disorders. The reason for this is the indirect antagonism of dopamine receptors, which provokes hyperprolactinemia.

Dapoxetine is approved for use in the treatment of premature ejaculation. In this case, the drug received approval due to its side effects. However, in some cases, antidepressants of this group provoke reverse ejaculation (retrograde ejaculation of seminal fluid occurs proximally into the bladder, which can lead to inflammatory processes). Activation of serotonin receptors also affects the dopamine system: patients feel more tired (activation of 5-HT2C receptors reduces the release of dopamine). Excess serotonin provokes tremors, headaches and osteoporosis, as well as pseudocholinergic dry mouth and particularly severe sweating of the scalp. An interesting fact is the following: at one time it was observed that an increase in determination and thirst for action with drugs of this group increased the number of suicides. It was assumed that increased readiness to act led to the fact that patients with depression were more likely to decide to commit suicide. But later, one large British study refuted this statement, proving that self-abstinence from drugs increases the number of suicides.

Separately, it is worth noting the drug bupropion (dosage 150-300 mg per day, half-life 20-37 hours, active metabolites - hydroxybuproprion, threohydrobuproprion, erythrohydrobuproprion), which is mainly an inhibitor of the reuptake of norepinephrine and dopamine, but also affects other transmitter systems . It is worth noting that its use does not lead to weight gain and only slightly affects sexual functions. This drug is also approved for use in the treatment of nicotine addiction.

Sources

1. Herdegen T. et al. Kurzlehrbuch Pharmakologie und Toxikologie. – Georg Thieme Verlag, 2013.
2. Diener HC Klinische Pharmakologie. – Georg Thieme Verlag, 2011.

Sertraline

Sertraline (Zoloft, Stimuloton, Asentra) is characterized by a thymoanaleptic (anxiolytic) effect of moderate severity. There are no vegetative stabilizing, sedative, timerectic, adrenergic and anticholinergic (muscarinic) effects. The drug does not affect psychomotor functions, has a weak antiphobic and very weak hypotensive effect.

Indications for use are mild to moderately severe melancholy depression with secondary anxiety and somatoform disorders. After obtaining a satisfactory effect, continuing treatment with sertraline helps prevent relapse of depression or its subsequent occurrence.

Sertraline is also used to treat obsessive-compulsive disorder (OCD).

As a rule, the antidepressant effect occurs after one week of therapy.

After achieving the initial effect, long-term treatment with sertraline for up to 2 years ensures its sufficient effectiveness and good tolerability. Sertraline is used to treat panic disorders and post-traumatic stress disorder syndrome (PTSD). The initial therapeutic effect in this case may appear within 7 days, but the full effect is usually achieved later - after 2-4 weeks (possibly over a longer period of time, especially with OCD). There is a point of view according to which the drug usually reduces secondary anxiety associated with melancholy depression.

Sertraline (Zoloft, Stimuloton) is a relatively low-toxic antidepressant from the SSRI group; it is used in child psychiatry, as well as in cases of depressive spectrum disorders that develop after an acute episode of schizophrenia.

Sertraline is prescribed in a dose of 50 mg. per day (usually once a day in the morning, regardless of meals). The dose can be increased by 50 mg. in Week. Recommended daily doses: for inpatient treatment of depression - 50-100 mg, for outpatient use - 25-50 mg. If necessary, the dose is increased at intervals of 2-4 weeks (maximum daily dose - 200 mg).

At therapeutic doses, sertraline inhibits the uptake of serotonin by platelets. It is extensively metabolized in the liver, approximately 98% of it is present in the body in protein-bound form, and its main metabolite has weak pharmacological activity. Unlike most antidepressants, it binds preferentially to a1-glycoprotein, whereas other drugs interact primarily with albumin.

The half-life of sertraline is influenced by age. In children, sertraline metabolism is more active (Warrington S.1988). Considering the latter circumstance, it is recommended to use the drug in children in a lower dose to avoid excessive levels of its concentration in plasma. At the same time, according to other authors, the pharmacokinetic profile in adolescents and elderly people does not differ significantly from the profile of patients aged 18 to 65 years.

Sertraline is slowly absorbed over 4-6 hours, eliminated through the gastrointestinal tract and kidneys, the equilibrium concentration of the drug is achieved within one week after the start of treatment.

The average half-life of sertraline is 22-36 hours. Steady-state concentrations of sertraline are established after 1 week of treatment.

Kidney pathology has almost no effect on the clearance of sertraline. At the same time, with liver pathology, the half-life of sertraline in serum, as well as its concentration in plasma, increases by almost 50%.

Side effects: tremor, nausea, dry mouth, diarrhea. Typically, side effects resolve spontaneously by the end of 4 weeks of therapy. Early unwanted side effects are especially common in the treatment of panic disorders.

Contraindications to the use of the drug are liver and kidney diseases with impaired function. After discontinuation of the drug, MAOIs are prescribed no earlier than 5 weeks later.

With chronic use of sertraline, addiction develops to it, since its prolonged use leads to a decrease in the number of its receptors (Anthony P., et al., 2002).

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are considered to be first-line drugs for the treatment of anxiety and depressive disorders. Despite the fact that all antidepressants from the SSRI group have the selective property of blocking the reuptake of serotonin (5-HT), they also have structural differences. We emphasize that these antidepressants exhibit minimal effect in relation to other neurotransmitters of the central nervous system. SSRI antidepressants are rapidly absorbed and metabolized in the liver, but by different P450 enzymes. For comparison, fluoxetine has an active metabolite, is actively metabolized in the liver, t1/2-h (active metabolite) = 72 (200), inhibition is carried out by isoenzymes 2D6, 3A4, 2C19; fluvoxamine, on the contrary, does not have an active metabolite, t1/2-h is 15 hours, and inhibition is carried out by isoenzymes 1A2, 2C19; paroxetine - has no active metabolite, t1/2-h - 20 hours, inhibition due to 2D6, 2C9; sertraline has a weak active metabolite, t1/2-h - 25 (66), mild inhibition is carried out by isoenzyme 2D6; citalopram and escitalopram have a t1/2-h of 36 hours.

Low concentrations in breast milk, in addition to high levels of fluoxetine and citalopram), especially paroxetine, and to a lesser extent fluoxetine, allow these drugs to be used in cases of emergency, and in nursing mothers. Withdrawal syndrome is more pronounced with paroxetine, less so with fluoxetine, however, in all cases it takes a short period of time.

There are no precise indications in the literature on the direct dependence of the effect on the dose taken in cases of using selective serotonin reuptake inhibitors; escitalopram may be an exception to this situation), therefore, most often, when taking SSRIs, preliminary titration of the dose of these drugs is not required.

SSRIs are more often recommended for use in old age, in the presence of anxiety spectrum disorders comorbid with depression, in particular, in obsessive-compulsive disorder (OCD), in the presence of suicidal behavior (the risk of overdose of these drugs is much less than that of tricyclic antidepressants). Escitalopram (S is the enantiomer of citalopram) is considered a more effective drug than citalopram. Escitalopram binds two serotonin reuptake sites (orthosteric and allosteric), which leads to conformational changes in the transporter and increased reuptake blockade. The R enantiomer of citalopram blocks these conformational changes, which is not typical for other drugs from the SSRI group.

Unfortunately, antidepressants from the SSRI group have a large number of side effects: gastrointestinal (nausea occurs most often here, vomiting, diarrhea, constipation (activation of postsynaptic 5-HT3 receptors), sedative (often accompanied by dizziness - 10%-20%), cause sexual dysfunction (common for men and women, possibly due to activation of 5-HT2 receptors, the latter are observed to a greater extent with paroxetine, to a lesser extent with citalopram and fluvoxamine), hyponatremia (the highest risk is observed in elderly patients, primarily for due to inadequate secretion of antidiuretic hormone - SIADH), agitation, movement disorders, parkinsonism (rarely), rarely seizures. In addition, selective serotonin reuptake inhibitors, in particular citalopram and escitalopram, are associated with a dose-dependent effect in relation to an increase in the QTc segment by electrocardiogram, and also increase the risk of bleeding by reducing platelet serotonin (if the risk of bleeding is high, gastroprotective drugs are prescribed).

There are works in the literature that indicate the usefulness of combining antidepressants from the SSRI group with tricyclic antidepressants, lithium, L-tryptophan (in the latter case, caution should be exercised). Combinations of antidepressants from the SSRI group with monoamine oxidase inhibitors and L-tryptophan are problematic due to the risk of developing serotonin syndrome. SSRIs are capable of inhibiting CYP2D6, CYPA3/A4, thereby increasing the blood concentrations of antipsychotics, opiates and tricyclic antidepressants. Fluvoxamine inhibits CYP1A2 and therefore increases plasma concentrations of clozapine, theophylline and caffeine.