Antidepressants  are psychotropic drugs used primarily for depression therapy , affecting the level of neurotransmitters , in particular serotonin , norepinephrineand dopamine . In a depressed patient they improve mood , reduce or relieve anguish, lethargy, apathy , anxiety , anxiety, irritability and emotional tension, increase mental activity, normalize the phase structure and duration of sleep , appetite.

This is the so-called thymoleptic action ( Latin  thymoleptica , from the Greek θυμός “soul, mood” + ληπτικός “absorbing, retracting”) – the term was proposed in 1958 by P. Kielholz and R. Battegai (German). ) .  

Many antidepressants do not cause mood improvement in a person who does not suffer from depression .

There are studies that question the effectiveness of antidepressants in depression like against panic, or data that the difference between antidepressant and placebo is very modest, and studies that show that the difference between antidepressants and placebo achieves clinical significance only with very severe depression.

cheme of action

The main effect of antidepressants is that they block the disintegration of monoamines ( serotonin , norepinephrine , dopamine ,phenylethylamine , etc.) under the action of monoamine oxidases (MAO) or block the reverse neuronal capture of monoamines.In accordance with modern ideas , one of the leading mechanisms for the development of depression is the lack of monoamines in the synaptic cleft  – in particular serotonin and dopamine . With the help of antidepressants, the concentration of these mediators increases in the synaptic cleft, because of this their effects are intensified.

It is necessary to note the presence of the so-called “antidepressant threshold”, which is individual for each patient. Below this threshold, antidepressant effect is absent and only non-specific effects, in particular side effects, sedative and stimulating properties are manifested. Modern data indicate that for the manifestation of antidepressant action in drugs that reduce the reuptake of monoamine, it is necessary to reduce the capture by 5-10 times. To demonstrate the antidepressant effect of drugs that reduce the activity of MAO, you need to reduce it by about 2 times .

However, modern research shows that there are other mechanisms of action of antidepressants. For example, it is suggested that some antidepressants reduce the stress hyperreactivity of the hypothalamo – pituitary – adrenal system [4][ unauthorized source? ]. Some of them may be antagonists of NMDA-receptor , reducing undesirable toxic effects in depression glutamate . There are data on the interaction of such antidepressants as paroxetine , venlafaxine and mirtazapine , with opioid receptors , which is indicated by the presence of antinociceptive effect and significant containment when using naloxone  -an antagonist of opioid receptors in experiments . Some studies suggest that some antidepressants reduce the concentration of substance P in the central nervous system . But for today the most important mechanism for the development of depression, which affects all antidepressants, consider insufficient activity of monoamines .

History

The isolation of antidepressant drugs (antidepressants) into an independent pharmacological group occurred in the 1950s with the discovery of synthetic preparations of both iproniazide and imipramine , which have a timoanaleptic effect. Until that time, various natural opiates and synthetic amphetamines were used as antidepressants , which disappeared from use due to a large number of side effects [11] , bromides , barbiturates , and alkaloids isolated fromrauwolfia plants and St. John’s Wort , now attributed to other pharmacotherapeutic groups.

Amphetamines were used in patients with severe psychomotor retardation, opiates, bromides and barbiturates – withagitated mental states. The effectiveness of such therapy was very doubtful  .

Alkaloids 

Plants containing alkaloids, from ancient times used by man for medicinal purposes. In the 1950s, psychopharmacologists began an active study of the indole alkaloid reserpine , isolated from the plant rauwolfia , which exhibited neuroleptic activity. For some time reserpine was used for the treatment of mental illnesses, but subsequently the attention of psychopharmacologists was turned to another indole derivative, β-carboline . Over the period 1952-1962, more than 300 publications were devoted to carbolines in the world literature .

In 1921, Perkin and co-workers, when trying to synthesize β-carboline derivatives from indole-2-carboxylic acid, unexpectedly obtained the first pyrazinoindole derivative, but no information on the biological activity of this substance was obtained at that time. In the 1960s, this compound served as the basis for the synthesis of the original Soviet antidepressant pyrazidol in VNIKhFI .

Preparations of St. John’s wort

Preparations of St. John’s Wort have been used since the time of antiquity in the treatment of depression, insomnia and anxiety ( Latin,  Hypericum perforatum L. ,English  St John’s Wort ): extracts , tinctures , decoctions , etc. Hypericum amaloids are still used today for the treatment of depressive conditions . For the first time, St. John’s wort preparations were licensed according to indications of depression, insomnia and anxiety in 1998 in Germany and Austria and immediately gained popularity, in 1999, gaining leadership in the volume of medicinal sales. Their effectiveness in mild and moderate depressions is comparable with the effectiveness of standard antidepressants (antidepressants of the TCA group and the SSRI group) . Only with severe depression, St. John’s wort appears to be inferior to standard antidepressants by timoleptic activity and, probably, does not exceed placebo.

The efficacy of St. John’s wort in the treatment of depression has been proven by numerous clinical trials and several meta-analyzes – in particular, a meta-analysis of more than 20 studies involving more than 1500 people , and Cochrane a survey of 29 studies in which 5,489 people participated . In the UK,in 23 randomized, double-blind studies, St. John’s wort was compared with placebo and standard antidepressants in the treatment of mild and moderate depressive disorders in 1757 outpatients . The results of the study showed that St. John’s wort extract with mild or moderate depression is more effective than placebo, and is as effective as conventional antidepressants .

St John’s worts are more safe and better tolerated than standard antidepressants ; the side effects that led to the withdrawal of the drug in clinical trials with the intake of St. John’s wort were less common . Nevertheless, when he is taken, fatigue, anxiety, confusion, gastrointestinal disorders, dry mouth, redness of the skin, itching, photosensitivity may occur . As with the use of other antidepressants, manic states may develop in patients with bipolar depression . When treating St. John’s wort, simultaneous use of SSRIs and MAO inhibitors should be avoided  .

Many different preparations of St. John’s wort are usually available in the pharmacy network without a prescription, and they differ in the amount, concentration and ratio of active and inactive, useful and potentially harmful components  . The specific medicinal forms of St. John’s wort may differ significantly from those studied in clinical trials . Some of the preparations contain only small amounts of biologically active components .

Isoniazid and imipramine

In 1951 in New York ( USA ), two clinical trials of new anti-TB drugs have been launched – isoniazid and iproniazid . At first, only patients with poor prognosis were subjected to these tests, however, they also proved to be highly effective in their preparations. In addition, the researchers noted that patients with treatment with these drugs experienced mild exaltation, began to show an excess of strength, and some even began to violate public order in the hospital . The drugs seemed interesting to the world medical community, they began to be actively discussed. Interested in the influence of drugs on the mood of patients. In 1952, the French psychiatrist Jean Deleu reported on the positive results of treating depression with isoniazid. In the same year, following the Dele, American psychiatrist Max Lurie decided to try using isoniazid to correct the depressive state. The following year, Lurie and his colleague Harry Zalzer reported that in 60% of cases the drug was effective and successfully corrected the depression. M. Lurie and G. Salzzer first proposed to call this effect antidepressant, and the drugs themselves antidepressants (1953) .

Despite the fact that isoniazid is the first synthetic antidepressant, the mechanism of its action is unknown to date. It is suggested that it blocks the enzyme diaminoksidazu , and also has a weak inhibitory effect on monoamine oxidase A .

A few years before the discovery of the Americans, in 1948, the laboratories of the Swiss firm Geigy synthesized the ancestor of a group of tricyclic antidepressants, imipramine . In 1950, his clinical studies began, but until 1954 the drug was not used in clinical practice, while the impressive results obtained with the use of a chemically close tricyclic compound, the antipsychotic chlorpromazine , did not attract attention to it . From 1954 to 1957, imipramine was treated by more than 500 patients at the R. Koon Clinic in Switzerland . Later, imipramine was widely used, and its generics were synthesized .

The first synthetic antidepressants were introduced into medical practice in the mid-1950s and were dispensed only by prescription . Then it was believed that only 50-100 people from a million people suffer from depression, so the pharmaceutical firms did not show a pronounced interest in antidepressants. Sales of these drugs in the 1960s were incomparable in volume with sales of antipsychotic and benzodiazepine drugs .

New generations 

In the 1960s, selective monoamine oxidase inhibitors appeared , as well as selective inhibitors of reverse neuronal seizure of serotonin . In the future, the main direction in creating new antidepressants was a reduction in side effects, as well as a strengthening of the main ones. This is achieved by increasing the selectivity of the action of the drugs on the “necessary” receptors. In the 1990s, selective action drugs were synthesized that had fewer side effects.

Soviet and Russian antidepressants 

Soviet pharmaceuticals tried to keep up with the achievements of foreign psychopharmacologists. After the discovery of iproniazide and imipramine in the late 1950s at the All-Union Scientific Research Chemical-Pharmaceutical Institute. Sergo Ordzhonikidze (VNIKhFI) began work on reproducing these drugs. Iproniazide was reproduced in the USSR under the trade name “Iprazid” (in the form of tablets), and imipramine was marketed under the trade name “Imizin” (in the form of a solution for injections and tablets). Industrial production of imizin was started in 1964.

Shortly before this, in 1963, the USSR Pharmacological Committee recommended the preparation “Hemofyrin”, which is a 0.2% solution of hematoporphyrin , obtained from human red blood cells, as an antidepressant in medical practice . Being a biological catalyst , hemofirin proved to be effective in asthenic , asthenic-hypochondriacal and astheno-depressive states of various genesis. At the same time, the relatively short shelf life of the finished product (1 year), as well as the rather rapid appearance of synthetic antidepressants, did not allow it to play a significant role in the treatment of depression. In the 1980s, the use of hemofirinceased in connection with the detection of cases of infection of blood products with human immunodeficiency virus .

Conducted in VNIKhFI systematic study of psychotropic substances and the work on the synthesis of alkaloids allowed Soviet scientists to create an original drug indopan , stimulating the central nervous system and is used to treat depression, which in its class refers to the non-selective MAO inhibitors . Indopan was allowed to be used in medical practice and industrial production in the USSR in 1964 . Because of the serious side effects of psychedelic and hallucinogenic effects, indopan has not been widely used and is not currently produced. Since 1970, the neuroleptic carbidine has been used as an antidepressant in the USSR .

Azafen and pyrazidol 

The first original Soviet antidepressant of the tricyclic structure is azafen , to which WHO subsequently appropriated theinternational non-proprietary name pipofezin. Azafen was developed in VNIIKhFI in the laboratory of synthesis of antituberculous compounds under the guidance of MN Shchukina and studied in the laboratory of pharmacology under the guidance of MD Mashkovsky . It is allowed to medical use in the USSR since 1970 . The drug has found application in the treatment of various depressions and neurotic disorders, is effective primarily in the case of depression of mild and moderate severity . Azafen is usually well tolerated, which allowed it to be used in outpatient practice, and as a “cure” remedy after treatment with other antidepressants.Rarely, mostly at the beginning of therapy or at high doses, there are usually mild side effects such as weakness, fatigue, drowsiness, attention deficit disorder,tachycardia , headache, dry mouth, tremor , dizziness, decreased libido . Has a sedative effect; Characteristic for other tricyclics cholinolytic and cardiotoxic side effects are absent. In 1996, production of the drug in Russia was discontinued due to the lack of raw materials for its manufacture. Since 2005, the production of azafen in Russia has been resumed .

Another original antidepressant is the drug pyrazidol , developed later in the VNIKhFI by MD Mashkovsky and NI Andreeva , which later received the international non-proprietary name pyrlindole. The drug has been approved for medical use in the USSR since 1975 . Pyrazidol is a tetracyclic compound, an indole derivativethat selectively inhibits MAO-A . The specific features of the drug include a combination of a timoleptic effect with a regulating effect on the central nervous system (an activating effect in patients with apathic depression and a sedative effect in patients with agitated conditions). In addition, it is claimed that pyrazidol has anootropic effect, improves cognitive (cognitive) functions. Side effects (dry mouth, tachycardia, sweating, dizziness, etc.), as a rule, are weakly expressed .Pyrazidol is produced in Russia to this day.

Pyrazidol has a weak evidence base (there are only a few small RCTs ) and is practically unknown in Western countries. The weakness of the evidence base and the unreliability of the therapeutic effect, as well as the unreasonably high cost of high doses of this drug (an unprofitable cost-effectiveness ratio) limit its use in clinical practice . Azafen also has a low level of evidence: there are only data from uncontrolled (open) studies .

Classification 

The following classification of antidepressants is most convenient for practical use :

  1. Means that block the neuronal capture of monoamines
    • Non-selective actions blocking the neuronal capture of serotonin and norepinephrine ( imipramine , amitriptyline )
    • Selective action
      • Blocking neuronal capture of serotonin ( fluoxetine )
      • Blocking neuronal seizure of norepinephrine ( maprotiline )
  2. Inhibitors of monoamine oxidase (MAO)
    • Non-selective action, inhibit MAO-A and MAO-B ( nialamide , transamin )
    • Selective action, inhibit MAO-A ( moclobemide ).
  3. Monoamine receptor agonists
    • Noradrenergic and specific serotonergic antidepressants
    • Specific serotonergic antidepressants

There are other classifications of antidepressants. For example, depending on the clinical effect,  :

  1. Antidepressant sedatives: trimipramine , doxepin , amoxapine , amitriptyline , azaphene , mianserin , trazodone , fluvoxamine , buspirone .
  2. Antidepressants of balanced action: maprotiline , tianeptine , sertraline , pyrazidol , clomipramine , venlafaxine , dosolepin , tryptophan .
  3. Antidepressant stimulants: imipramine , desipramine , nortriptyline , fluoxetine , moclobemide and other MAOI (with the exception of pyrazidol), heptral ,reboxetine , bupropion .

Unlike the actual antidepressant (timoleptic) effect, sedation or psychostimulant can develop in the first days of therapy. The appointment of antidepressant sedatives is advisable in case of predominance of anxiety and agitation in the structure of the depressive syndrome , stimulating – with inhibition and apathy ;balanced preparations can be used in both cases . Failure to comply with this principle may reduce the effectiveness of antidepressant therapy and even lead to weight gain.

Thus, the use of stimulant antidepressants in anxious depression or in complex anxiety-delusional syndromes can exacerbate anxiety, fear, psychomotor agitation , sleep disturbances, exacerbate psychotic symptoms; if the patient has suicidal thoughts, stimulating antidepressants can contribute to the realization of suicidal tendencies . With simple depressive syndromes, the activating effect of antidepressant stimulants helps to reduce inhibition, which can also lead toautoaggressive actions .

Antidepressants of balanced action have, as a rule, a dose-dependent balanced effect: the stimulating effect of these drugs is most often manifested when they are used in small and high doses, and sedative – when used in daily average doses. The exception is those of balanced antidepressants, for which a nedozozavisimy balanced effect with a predominantly sedative or stimulating effect (for example, milnacipran and pyrazidol ) .

It is worth noting that not all antidepressants can be clearly attributed to a particular group, depending on whether they have a stimulating, sedative or balanced effect. Citalopram some authors attributed to antidepressants balanced action, noting the presence of his antianxiety effect, others – to antidepressants, stimulants . Milnacipran is sometimes referred to as balanced antidepressants , other authors note a predominance of a psychostimulatory effect in its action . Mirtazapine is called a balanced drug or sedative, paroxetine – an antidepressant stimulant, a balanced or sedative drug.

Some drugs have, in addition to antidepressant, a pronounced antinociceptive (analgesic) effect; they also excrete antidepressants with pronounced anxiolytic (anti-anxiety) action.

 


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