Serotoninotropic drugs are drugs that affect serotonin receptors by inhibiting or stimulating serotonin production in the body. Antidepressants are a large subclass of serotoninotropic compounds, so this paper will focus mainly on antidepressants.

Antidepressants or thymoanaleptics are a group of psychotropic drugs with a predominant effect on pathologically depressed mood or depressive affect.

Serotoninotropic substances

They do not have an euphoric effect, as in healthy individuals do not cause mood swings. Antidepressants are used in a variety of diseases and various pathological conditions. Unconventional indications for thymoanaleptic therapy include:

  • a number of psychosomatic diseases (irritable bowel syndrome, peptic ulcer, bronchial asthma, neurodermatitis and other skin diseases);
  • obsessive-phobic disorders;
  • panic attacks and other worrying syndromes;
  • anorexia nervosa or bulimia;
  • narcolepsy;
  • various pain syndromes;
  • vegan-diencephalous crises;
  • hyperkinetic disorders in children;
  • chronic fatigue syndrome;
  • alcoholism and other substance abuse.

Epidemiology of depression

According to the World Health Organization, approximately 4-5% of the world's population suffers from depression, and the risk of a major depressive episode is 15-20%.

Depression is a chronic recurrent disease, with recurring episodes occurring in about 60% of patients. In 15% of observations, patients suffering from depression make suicide attempts, which is about 60% of all suicide attempts. This percentage is extremely high, and the mortality rate for depression is only slightly lower than that for cardiovascular disease. According to U.S. projections, by 2010-2030, depression, which is growing exponentially, will be in the 1st place in the world in terms of prevalence, bypassing cardiovascular disease. At the same time, only 20% of patients are looking for medical care, and most of them go to therapists. Those, in turn, are not always ready for proper diagnosis, so that only 30% of depressions (out of 20% of those who apply) are diagnosed in time and only 25% of patients receive the necessary antidepressant therapy. The tragedy of these figures is all the more evident when we consider the fact that in 60-70% of cases adequate treatment produces the desired effect.

Economic aspects of the disease

Direct costs for depression treatment in the U.S. alone in 1998 were $5.8 billion, with indirect costs of $39.8 billion [of which 28 billion were lost due to disability and 11.8 billion due to death (suicide)].

Thus, the total amount of expenses reached 45.6 billion dollars, with the cost of medicines not exceeding 3%. It is clear that properly performed therapy would not only save lives, but also avoid unjustified costs.

History of antidepressant therapy

As we know, thymoanaleptic therapy has emerged in a purely heuristic way, i.e. in a random way. Initially, R.G.Bloch in 1954 drew attention to the antidepressant properties of the known antituberculous drug iproniazid, and in 1957, R.Kuhn in studying the action of imipramine in depression first used the term "thymoanaleptic action", i.e. raising the mood. The chemical structure of imipramine is close to that of chlorpromazine, a previously discovered neuroleptic; however, imipramine found no antipsychotic properties. It was tried to be used as an antihistamine drug, was used in dermatology in the treatment of hives, and then its antidepressant effect was found. Following this, a large number of different antidepressants were synthesized, many of which are the basic means of treating depression.

General provisions

5-hydroxytryptamine (serotonin) is one of the physiologically active biogenic amines in animals and humans. Despite the widespread use of this biocatalyst in nature, its content is usually so low that until recently there was no known natural source from which to obtain it in any significant quantities. For the first time, natural serotonin was isolated in 1959 from the buckthorn bark.


Serotonin from tryptophan is formed, when at first under the influence of 3 tryptophanhydrosilase we get 5 - oxytryptophan (5-OTPh), and then with the help of decarboxylase - serotonin. Amines synthesized in human and animal bodies are contained in enterochromaffin cells of the intestine (up to 90% of the total amount), in platelets, fat cells, skin, lung tissue, spleen, kidneys, liver. In the CNS more serotonin is found in the hypothalamus and middle brain, less in the thalamus, hypokamis cerebellum neocortex and gray matter of the spinal cord.

Serotonin accumulates in cellular depots in the form of granules (up to 5%) and in free form (up to 25%).

Serotonin occupies one of the first places among other physiologically active substances by the number and variety of functions it performs. One of the main properties is its ability to cause contraction of the clutch muscles (blood vessels, bronchi, stomach, uterus), stimulate sympathetic ganglia to increase blood thromboplastic activity.

Serotonin is used as a medicinal product. The effect is related to the peripheral vasoconstrictive action, the ability to increase platelet aggregation and shorten bleeding time.

It is used to treat hemorrhagic syndrome in various pathological conditions, including Werlhof disease, hypo- and aplastic anemia, thrombasthenia, hemorrhagic vasculitis, hemorrhagic syndrome in the treatment of cytostatic agents in oncology. Serotonin helps to increase the resistance of capillaries and reduce the duration of bleeding.

Serotonin is used in the treatment of malignant tumors in conjunction with X-ray therapy.

As a result of the experiment, the antitumor activity of serotonin in relation to Ehrlich's tumor, Jensen's sarcoma, Heren's carcioma, melanoma of Garding-Passi was established. The effect of serotonin on the tumor is based on a selective reduction in blood supply to tumors.

Physiological role of serotonin in the CNS is proven:

  1. in the regulation of cycles of sleep - waking and in the organization of slow - wave sleep;
  2. in the mechanism of pain perception (pain sensitivity decreases with increasing amine content, i.e., with activation of serotoninergic structures in the brain system);
  3. in the regulation of sexual behavior (reduction of serotonin levels in the brain leads to increased sexual activity and vice versa;
  4. in the mechanisms of formation of the Emotional state and memory (serotonin promotes the transition of the neurodynamic phase of fixation of memory traces into the phase of structural and metabolic changes, i.e., transformation of short-term memory into long-term memory).

In addition, serotonin metabolic disorder is thought to be of importance in the pathogenesis of depressive states of schizophrenia and epilepsy (mainly amine deficiency).

Functional failure of the serotoninergic system of the brain obviously serves as a major pathogenetic factor in the development of hyperkinesis. It is also shown that during migraine attacks in the blood and brain serotonin content drops, and after the attack - increases, although found good prophylactic efficacy of some direct antonists of this amine. Weighted role of serotonin as a mediator of inflammation and allergic reactions.

Since the list is so long and includes such a wide range of everyday reactions (from oppressed mood to extreme aggressiveness), some of the researchers are inclined to believe that it is possible to understand how serotonin works in the body of a healthy and sick person, only if we proceed from the norm - its usual role and regulation of mood, mental motivation and appetite. When the serotonin system is brought out of balance, the consequences are very different. Depending on the genetic predisposition to environmental influences, this imbalance finds its final expression in migraine, overeating, alcoholism, obsessive-depressive syndrome, depression itself or loss of control over impulses.

Of course, you will ask: "Why?", "How does it work?", "Who said that?", and the main thing is "What can you prove? There are answers to some of them for you. The very first question will surely sound like this: "What is special about this very Serotonin?

Serotonin is a neurotransmitter, a complex organic substance whose molecules interconnect and interact with the cells of nervous tissue. Without neurotransmitters, we would not be able to think, feel, move and live in general. Serotonin also does double work in the cardiovascular and gastrointestinal systems. It helps regulate the expansion and contraction of blood vessels, and also provides the function of platelets, blood plaques that give blood clotting, so that the closure and healing of wounds. Serotonin also forces the reduction of smooth muscles, contributing to the promotion of food through the intestinal tract in the digestive process.

To date, about thirty neurotransmitters have been identified. All these neurotransmitters work together to form our thoughts, feelings, decisions and actions. Although the cortex, our well known wrinkled "gray matter," is fully responsible for all "executive" decisions, the brain seems to rely on democratic principles in its work. Many brain centers are involved in processing the raw information that helps the brain determine when to eat and sleep, when to feel pain, when to experience a decline in strength, or when to feel upbeat and in mood. Multiple neurotransmitters and brain centers form a system to monitor and compare information. It is safe to assume that more than one transmitter and more than one group of nerve cells are connected to each of the many urgent brain tasks. This makes it possible and possible to "pick up" the function by the doubler if the main center or the neurotransmitter does not work for some reason. One of the main roles of serotonin is to control the efficiency of other neurotransmitters. Essentially, serotonin is used to sort and prioritize messages sent with other neurotransmitters: it is serotonin that gives them "red, yellow or green light". This explains why serotonin has such a deep and strong effect on our mood and behavior, although it does not work alone. Here it is appropriate to remember the statement of Thomas Carj, a scientist from Yale University: "Serotonin is only one of the orchestras of the molecular orchestra. But it is not a trumpeter or a cellist, but rather a conductor who organizes the well-coordinated work of the brain".

Study of the action of tryptophan

After it was found that antidepressants have adrenal and serotoninopositive effects and the pathogenesis of endogenous depression is associated with a deficit of noradrenaline and serotonin, it was natural to use these monoamines as an antidepressant. However, because serotonin and noradrenaline do not penetrate the hematoencephalic barrier, their predecessors, tryptophan, 5-oxytryptophan (5-OTP) and DOPHA, were used to treat depression, which pass well to the brain cells. The essential amino acid tryptophan turns into 5-OTP, which in turn turns into serotonin (5-oxytryptopamine). DOPHA is formed from the essential amino acid tyrosine and turns into dopamine, which is a mediator of dopaminergic neurons and a precursor of noradrenaline. All biogenic amines and their precursors in the living organism are left-rotational isomers. Part of the food-supplied tryptophan is exposed in the liver to tryptophanpirrolase, which activates the oxidation of tryptophan (kinurenin pathway), resulting in a decrease in its proportion, going to the synthesis of 5-OTPH and, further, serotonin. Tryptophanpirolase is activated by glucocorticoids (positive induction of the enzyme), so under stress and in the morning hours when the cortisol level is increased, more tryptophan is metabolized along the kinurenine pathway. Tryptophanpirrolase is also induced by the substrate, i.e. tryptophan. In plasma, tryptophan is in the associated form with albumins. Non-esterified fatty acids compete with tryptophan for albumins, and increasing their level in plasma leads to an increase in free tryptophan concentration. The limiting enzyme in serotonin synthesis is tryptophanhydroxylaze, which turns tryptophan into 5-OTF, but this enzyme is not saturated with the substrate normally.

Therefore, the speed of tryptophan transport through the hematoencephalytic barrier plays an important role in the formation of serotonin in the brain.

The precursors of serotonin tryptophan and 5-OTP used in the treatment of depression for almost 20 years, but still the data on their effectiveness remain controversial. Thus, N. Van Praag (1982) gives summary data of 14 works on 5-OTF application, with positive results obtained in 12 studies, and negative results in two studies. Antidepressant effect of 5-OTF in doses from 50 to 3000 mg per day was found in 191 of 350 patients treated.

However, in the review article R. published 2 years earlier. Tissot, H. Shafner (1980) presents the results of 5 studies, 3 of which had no positive effect at all, and 2 of which were uncertain. A comparison of these reviews shows how difficult it is to obtain a reliable picture of the therapeutic effects of psychotropic drugs based only on literature data, and how the authors' theoretical attitudes influence the selection and evaluation of other people's works.

In his own studies, N. Van Praag compared 5-OTP with the most powerful tricyclic antidepressant - chlorimipramine - and concluded that they are equally effective in treating "vitally depressed" - unipolar and bipolar, and their combination has a stronger antidepressant effect than each drug individually.

The daily dose of 5-OTF in this study was only 200 mg, but it was used in combination with a peripheral decarboxylase inhibitor, which reduced the conversion of 5-OTF to serotonin at the periphery and thus increased its supply to the brain.

The data on antidepressant effect of 1-tryptophan are even more vague: the review by N. Van Praag (1982) presents the results of 10 works, and in 5 of them tryptophan was equal to imipramine or amitriptyline by its therapeutic effect, in 3 - there was no antidepressant effect, and in 2 - it exceeded placebo. The effectiveness of tryptophan in the bipolar flow of TIR was significantly higher than in the monopolar flow. Doses of tryptophan were from 3 to 16 g per day. In most papers, it was used in combination with ascorbic acid, pyridoxine, and in one - with nicotinamide.

According to N. Van Praag (1982), the antidepressant effect of 5-OTF is undoubted, while the therapeutic effect of tryptophan is weaker and in some cases - questionable. This difference is quite understandable, because 5-OTP is a direct precursor of serotonin, while tryptophan must first be transformed into 5-OTP, and, as mentioned earlier, a significant part of tryptophan can go through the kinurenin metabolism pathway, and the intensity of this transformation depends on a number of factors.

Thus, the use of 1-tryptophan as a stand-alone antidepressant appears to be of little potential, especially since, as our and literature data show, its therapeutic effect, when used for quite a long time, tends to be depleted, and the drug causes significant side effects.

There are various ways to improve the efficacy of tryptophan: for example, it was combined with ascorbic acid, but given that it activates the synthesis of corticoids that induce tryptophanpirrolase, the value of such a combination is questionable. Pyridoxine (vitamin B6), the enzyme of decarboxylase involved in serotonin synthesis, is most commonly used in combination with tryptophan. In recent years, together with tryptophan is usually prescribed two substances that inhibit tryptophanpirolase: nicotinamide and allopurinol. However, these data were obtained in experiments in vitro and on rats. A. Green and co-authors. (1980) showed that in humans, both drugs do not enhance the therapeutic effects of tryptophan. The most effective combination is a combination of tryptophan and MAO inhibitors (monoamine oxidase).

We have treated 22 patients with endogenous depression with 1-tryptophan. In 14 patients, the depressive conditions were characterized by a prolonged course (1 year or more), low therapeutic sensitivity and significant severity of symptoms. 16 patients received niamide in doses up to 300 mg/day before treatment with tryptophan, and their condition remained stable during the last 2 weeks. The rest of the patients received tryptophan "in pure form". Optimal daily doses of 1-tryptophan were 6...7 g. As a rule, their increase caused side effects and did not lead to further improvement of the patients' condition. Obviously, this can be explained by the fact that tryptophan, being a substrate of tryptophanpirrolase, activates this enzyme in large quantities. We distributed most of the dose during evening hours, when the cortisol level is minimal.

Effexor Molekule

In 2 out of 16 patients who received tryptophan together with niamide, after 1 ... 2 weeks there was a complete disappearance of depressive symptoms, which could not be associated with spontaneous remission, given the long duration of the phase and the fact that the first signs of improvement occurred a few days after the start of treatment with tryptophan, in 12 patients there was a significant reduction in depression. This improvement could not be attributed to the action of a single niamide, as it has not shown therapeutic effects in recent weeks. Given the unfavorable flow and resistance to therapy in the selected patients, the results are encouraging. In 6 patients who received only 1-tryptophan, the depth of depression was less and in 4 of them the phases were not prolonged. In 1 patient there was a complete disappearance of depressive symptoms and after 2-3 days there was a mania, and in 1 patient there was a significant improvement.

Thus, in practical terms, tryptophan is not effective enough as an antidepressant, but in some cases, it is resistant to therapy of depression, it can potentiate the action of MAO inhibitors. In addition, a study of the antidepressant effect of tryptophan is important for studying the pathogenesis of endogenous depression, since its therapeutic effects indicate the role of serotonin. Analysis of literature data and our own observations allow us to conclude that 1-tryptophan has a distinct, though not strong, antidepressant effect.

As for the antidepressant effect of DOFA, the opinion of most researchers is similar: this drug does not have a distinct therapeutic effect in endogenous depression. It is usually limited to an increase in motor activity, and in the bipolar course of TIR, depression can be changed by mania. At the same time, there is evidence of weightiness and the emergence of depressive symptoms during prolonged DOFA treatment by reducing serotonin in the brain. The probable explanation for such a low efficacy of DOFA is that when this precursor is taken, the body increases the content of dopamine and its metabolites, but not Z-methoxy-4-oxyphenyl glycol - the main metabolite of noradrenaline in the central nervous system [Gelenberg A. et al., 1982], i.e. DOFA mainly goes to the synthesis of dopamine, not noradrenaline.

Serotonin syndrome

Serotonin syndrome is a potentially severe side effect of selective inhibitors of serotonin reverse capture.

Currently, there are many drugs known to affect serotonin metabolism (5-hydroxytryptamine, 5-NT), which are used to treat depression, anxiety, migraine, vomiting. Serotonin syndrome was first described by Oates and Sjoerdsma in 1960 in depressed patients. The number of reports about it is constantly increasing in the modern medical literature. This is due to the fact that the frequency of prescription of drugs affecting the serotoninergic system has increased.

Serotonin syndrome occurs mainly when prescribing combinations of different serotonergic remedies and is characterized by a triad of mental, neuromuscular and vegetative disorders. Theoretically, any of serotonergic drugs or their combination can provoke serotonin syndrome.

Most publications describe the development of serotonin syndrome using a combination of irreversible non-selective MAO inhibitors (monoamine oxidase) with such serotonergic drugs as antidepressants (clomipramine, imipramine), opioids (pethidine, dextromethorphan), L-tryptophan, lithium. In addition to MAO inhibitors, selective serotonin inversion neural capture inhibitors - SSRI (SSRI) - are among the drugs that can cause the development of this syndrome. This new class of antidepressants is increasingly being used in depression, obsessive-compulsive disorder, bulimia. They have less side effects and are less toxic than tricyclic antidepressants. The U.S. detention center prescribes antidepressants more frequently than tricyclic antidepressants. In Germany, 4 representatives of this class are used: citalopram, fluoxetine, fluvoxamine, paroxetine. Despite the fact that, on the whole, the SIHA is less likely to cause side effects than previously used antidepressants, treatment complications and dangerous interactions with other drugs are not uncommon for them. Serotonin syndrome is one of the serious complications of the SIZS therapy.

Serotonin syndrome in the treatment of SEZ

Serotonin syndrome during the treatment of the detention center usually occurs with simultaneous prescription with other serotonergic agents, most often with simultaneous or consecutive use with non-selective irreversible MAO inhibitors - isocarboxazide, phenylsine and trannylcypromin, as well as combine them with a selective reversible inhibitor MAO-A - moclobemide, selective reversible inhibitor MAO-B - selegiline, trasodone, nephasodone, lithium, clomipramine, amitriptyline. The development of serotonin syndrome may also provoke the simultaneous administration of SIZS with buspiron, carbamazepine, L-tryptophan, dextromethorphan, tramadol, used in migraine with dihydroergotamine and sumatriptan, antiparquinsonic drug levodopa. There are some reports of serotonin syndrome occurrence in the monotherapy of SIZS at the beginning of the therapy, with a sharp increase in their dosage or intoxication.

Clinic and diagnostics

The most frequent symptoms of serotonin syndrome are ataxia, myoclonia, hyperreflexia, hyperhidrosis, tremor, muscle stiffness, agitation, mental confusion. Changes in behavior are among its earliest symptoms and are often misinterpreted as worsening the course or aggravation of the underlying mental illness. This can lead to a dangerous increase in the dosage of the drug responsible for the syndrome.

The clinical picture of serotonin syndrome may include other symptoms: hyperthermia (more than 40.5°C), which is a life-threatening condition for some patients, epileptiform seizures, respiratory failure, disseminated intravascular coagulopathy, rhabdomyolysis, hepatic, renal and multi-organ failure. At least 12 deaths from serotonin syndrome have been described in the literature.

The syndrome usually develops shortly after increasing the dose of the drug or adding another drug with serotoninergic effect. In half of the published cases, symptoms occurred within the first two hours, in 25% - later than a day after changing the dosing regime. Separate reports described the syndrome appearance after cancellation of the prescription of MAO inhibitors, the latter were prescribed a few weeks after the cancellation of the prescription. Most often this happens after the prescription of fluoxetine, because it itself has a half-life of 1 - 3 days, and its active metabolite norfluoxetine - 1 - 3 weeks. Norfluoxetine can be found in the blood even 6 weeks after the elimination of fluoxetine. Based on these data, it is recommended to take a break between cancellation of the detention center and prescription of MAO inhibitors or other serotonergic substances: for fluoxetine - 5 weeks (for elderly patients - 8 weeks), for sertralin, paroxetine and fluvoxamine - 2 weeks.

Possible clinical and clinical and chemical manifestations of serotonin syndrome.

  • Changes in mental status:
    • Agitation, anxiety, delirium, euphoria, manic syndrome, hallucinations, mental confusion, mutism, coma.
  • Symptoms of vegetative dysfunction:
    • Abdominal pain, diarrhea, hyperthermia (from subfembrilitis to 42° and above), headaches, tears, mydriasis, nausea, tachycardia, tachypnea, fluctuations in blood pressure.
  • Nerve-muscular disorders:
    • Akatization, bilateral symptom of Babinsky, epileptiform seizures, hyperreflexia, myoclonia coordination disorders, horizontal and nystagmus nystagmus, ocologic crises, opistotonus, parasthesias, muscle rehydration, tremor.
  • Secondary complications:
    • Elevated concentration of creatine kinin, dispersive intravascular coagulopathy, myoglobinuria, renal, hepatic and multi-organ failure, rhabdomyolysis.

There are no specific laboratory studies whose data could be used in the diagnosis of serotonin syndrome. They are important for diagnostics of complications (metabolic acidosis, dispersion of intravascular coagulopathy, rhabdomyolysis) and observation of patients. Determination of plasma concentrations of serotonergic drugs does not play a special role, as in most cases of serotonin syndrome they do not exceed the permissible level, and their presence in toxic concentrations is not a prerequisite for its development. The diagnosis is based on clinical symptoms, the specifics of the action of drugs taken and the results of excluding diseases with a similar clinical picture.

Sternbach proposed the following criteria for serotonin syndrome diagnosis:

  • at least 3 of the symptoms described below are related to the beginning of treatment with serotonergic substance, or its increased dose, or the addition of another serotonergic substance:
    • Fever agitation

    • Hyperreflexion of Myoclonia
    • Diarrhea Coordination disorders
    • Diaphoresis (Hyperhidrosis. - Ed.) Amazing chill.
    • Changes in mental status (confusion, hypomania) Tremor
  • other possible causes - infections, metabolic disorders, drug intoxication, withdrawal syndrome, etc. - are excluded;
  • immediately before the onset of symptoms, the patient was not prescribed neuroleptic or increased dose (if it was prescribed long ago).

Differential Diagnosis

First of all, it is necessary to differentiate serotonin syndrome and such conditions as encephalitis, malignant neuroleptic syndrome (MNS), malignant hyperthermia, catatonia, and various intoxications. Because of the similarity of the clinical picture of serotonin syndrome and MNS, it is sometimes difficult to differentiate these conditions. NNS is an idiosyncratic reaction in the use of neuroleptics - most often neuroleptics with a pronounced effect on D2-receptors and, especially, depo-neuroleptics. NNS practically never occurs in monotherapy with antidepressants. NNS is characterized by changes in mental status, severe hyperthermia, muscle stiffness, vegetative disorders (blood pressure fluctuations, arrhythmias).

The conditions to be distinguished from serotonin syndrome:

  • Diseases (conditions) Intoxication
  • Encephalitis Cholinolytics
  • Hyperthyroidism Amphetamines
  • Hypertensive crisis in Lithuania
  • LSD Catatonia
  • Malignant neuroleptic syndrome Cocaine
  • Malignant hyperthermia with MAO inhibitors
  • Septicaemia Phencyclidine
  • Rigid Man Syndrome by Salicylates
  • Tetanus Strychnine

The latency period, from the prescription of neuroleptic or increasing its dose to the appearance of signs of MNS, usually lasts from 3 to 9 days. The concentration of creatine kinase is increased in almost all patients with MNS. Some patients also have rhabdomyolysis, myoglobinuria and polymorphonuclear leukocytosis.

Thus, both patients with MNS and patients with serotonin syndrome have hyperthermia, muscle stiffness, vegetative disorders, changes in mental state, increased creatine kinase activity. Serotonin syndrome can be characterized as a primary hypersexual rotonergic state, while NTS occurs mainly due to the blockade of dopamine receptors.

The following criteria can be used for differentiation of NNS and serotonin syndrome:

  1. Serotonin syndrome usually debuts with a pronounced psychomotor excitation in the form of delirium, which is combined with arterial hypertension, myoclonia, hyperreflexia and epileptiform seizures. Patients with VNS have akinetic stupor, hyporeflexia and fluctuating blood pressure;
  2. in serotonin syndrome, symptoms develop faster (more often within a few hours after prescription or increase in dose);
  3. hyperthermia, increased creatine kinase and leukocytosis in MNS are more pronounced than in serotonin syndrome;
  4. there is no mydriasis in ZNS.

Based on the general clinical picture of both states, we can assume that the pathophysiological mechanisms of their development are similar.


Serotonin syndrome more often occurs on the combined prescription of serotonergic medicines. This leads to an increase in serotonin concentration in the CNS through various mechanisms:

  • Increase in the synthesis of serotonin (L-tryptophan).
  • Direct effect on serotonin receptors (lithium, buspiron).
  • Increase of serotonin release from presynaptic membrane (ethanol, cocaine, dextromethorphan, pethidine, fenfluramin).
  • Reduction of serotonin backscatter (clomipramine, trazodone, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, dextromethorphan, pethidine, fenfluramin).
  • Reduction of serotonin decomposition (MAO inhibitors, imipramine).

Besides pharmacodynamic interactions, pharmacokinetic interactions also play a certain role. Fluoxetine, fluvoxamine, paroxetine and sertraline inhibit the activity of cytochrome-P450 isoenzymes to varying degrees. This leads to a slowdown in the metabolism of those serotoninergic substances that are a substrate for cytochrome P450, which may increase the risk of serotonin syndrome. Thus, Skop et al. described the development of serotonin syndrome after the simultaneous administration of paroxetine, which is a strong inhibitor of cytochrome P4502 D6, and dextromethorphane, which is a substrate and a reference substance for phenotyping CYP2 D6 polymorphism. In this case, along with the armacodynamic interactions, pharmacokinetic interactions seem to be also important.

The exact mechanisms of serotonin syndrome development are unknown. It is assumed that it develops by combined stimulation of 5-HT1A and 5-HT2-receptors. Serotonin can bind to numerous subtypes of pre and post-synaptic 5-HT receptors. Stimulation of these receptors in the dorsal and median nuclei of the suture of the brainstem and spinal cord plays an important role in the syndrome development mechanism. Congenital and acquired factors such as changes in peripheral serotonin metabolism, disorders of biotransformation of serotonergic substances, activation of other subtypes of serotonin receptors and interactions with other neurotransmitter systems may also play a role.


Popular prospective studies of serotonin syndrome are rare. There are no data on the frequency of its occurrence in general and in particular during the treatment of the detention center. The complete clinical picture of serotonin syndrome is probably quite rare. However, some of its symptoms appear quite often in patients receiving serotoninergic drugs. Serotonin syndrome is probably the final part of the spectrum of effects that occur during monotherapy or combined use of serotonergic medicines. A certain role is played by such factors as the initial clinical condition of the patient, the action of additional drugs, physical activity, which may lead to a patient's complete picture of serotonin syndrome.


There are no prospective studies regarding the treatment of serotonin syndrome. The treatment strategy relies mainly on data obtained from animal experiments or from descriptions of individual cases. Most often, the serotonin syndrome goes on without serious consequences. The main measure is the cancellation of all serotoninergic drugs, which in most patients leads to a rapid reduction of symptoms within 6 - 12 hours, and their complete disappearance within a day. Treatment in light cases includes hospitalization, to reduce myocloniums benzodiazepines (diazepam, lorazepam) are prescribed, to reduce body temperature paracetamol and external cooling is used. An increase in body temperature to 40.5°C or more indicates a threat to the patient's life. Such patients need intensive external cooling, endotracheal intubation, conversion to IVL and myorelaxant administration. Transfers to a TRS and myorelaxant administration can be effective in treating hyperthermia and preventing such complications as rhabdomyolysis and intravascular dissimilar coagulopathy. There have been reports of the efficacy of non-specific 5-NT1 and 5-NT2 receptors of mestisserhyd and ciproheptadine.


Serotonin syndrome is usually a favorable course, but in some cases it is a life-threatening complication in the treatment with serotoninergic means. A wide range of drugs, including SIZS, can lead to its development. To reduce the likelihood of its development, it is necessary, if possible, to abandon the combination of different serotonergic drugs or to conduct such treatment under strict medical supervision. Since there is no typical clinical picture of the syndrome, changes in mental status, vegetative and neuromuscular symptoms in patients treated in the SEZ should be considered as possible signs of serotonin syndrome. Immediate cancellation of all serotonergic substances leads in most cases to the rapid disappearance of symptoms.

History of the issue


Depression is not humanity's payback for sins or a fashionable disease that has emerged recently. We do not know when a person first felt its heavy length on his chest, but we know that people who lived in the Stone Age suffered from depressive disorders. This information was obtained as a result of extensive research conducted in the first half of the 20th century. At that time, there were still many deaf, untouched corners on Earth, where, according to the laws of the primitive communal system, people lived. The research showed that ancient people, as well as our contemporaries, were subject to various mental disorders, including depressive disorders.

Depression is as old as the world. Even the priests of Ancient Egypt in the 4th millennium BC were treating people who had a pathological state of longing. The priests of Ancient India believed that the despondency, like other mental diseases, was caused by obsession, and therefore, specially trained priests were engaged in exorcism of evil spirits.

The earliest surviving episode of depression can be found in the Bible. True, at that time there was neither the word "depression," nor the previously used word "melancholy," but there was a story about the first king of the Jews, Saul, who lived in the 11th century BC. It was an angry and gloomy man mired in despair: "and the Spirit of the Lord retreated from Saul, and outraged his evil spirit from the Lord" (Bible, chapter 16). As time went by, Saul was increasingly overwhelmed by attacks of gloomy moods, with light periods less and less frequent.

Saul's servants suggest that he will feel better if he hears the lute game. They find David, "a man who can play, a brave and belligerent man, and a man who is reasonable in his speeches and who is visible to himself. "More pleasant and better" becomes Saulu when David plays and soon "the evil spirit retreats from him. But a black envy for David eats Saul's heart, his self-love suffers more and more - everything that was so hard for Saul is easily given to David. The first thing that hurts him is that after the victory over the Philistines, people do not praise him, but David in their songs: "Saul exterminated thousands, and David exterminated tens of thousands. He is broken about the loss of recognition by the people and understands that these are the fruits of his work. He yearns for recognition and adoration from the people, but the understanding that this desire cannot be realized turns into a blind rage when he throws a spear at David. The spear flies by, and Saul feels fear and hatred towards David. David becomes "his enemy for life.

In this biblical story, there are clear signs of depression. It is primarily a gloomy, depressed mood, aggression, fear, hatred, envy. Also among the reasons for Saul's "depressed" mood is his feeling of guilt before God, because once he broke the word of God. All this makes Saul more and more depressed and eventually leads to the fact that Saul commits suicide by throwing himself on the sword.

Many places in the Book of Psalms testify that David himself was also attacked by a heavy pressure of depression. "There is no peace in my bones from my sins; I am completely drowsy, I walk all day complaining; I am exhausted and overwhelmed; I scream from the torment of my heart" (Psalm "I am weary of my sighs, every night I wash my bed, and with my tears I wet my bed" (Psalm 6.7). "Do not move away from me, for grief is close, and there is no helper!" (Ps.6.7). (Psalm 21.12) and others. Sad is the verse of King Solomon, telling about the vanity of vanities.

Ancient Greece

As far back as Homer's "Iliad" (7-8 B.C.) has a description of depression, when the hero Bellerophonte "wandered around the Aley Field, lonely, with his heart hungry, running away from the traces of man.

In his works, the great philosopher and physician Pythagoras Samoski (570-500 BC) recommended to leave people at attacks of sadness or anger and, left alone, to "digest" this feeling, having achieved peace of mind. He was also the first adherent of music therapy in history, recommending in hours of despondency to listen to music, in particular the hymns of Hesiod.

Democritus (460-370 BC) recommended in moments of sadness to contemplate the world and analyze your own life. This allows you to get rid of your passions, because, as he believed, they are what all the troubles are about.

The term depression itself (from Latin depressio - suppression) appeared relatively recently - in the XIX century. For more than two thousand years, depression has been called melancholy. This term was first introduced by the great ancient doctor Hippocrates (460-370 BC). Melancholia, translated from Greek, literally means melaina chole - black bile.

Hippocrates gave two meanings to the word "melancholy". First - melancholic he denoted one of the four temperaments of man, in the body which is dominated by black bile - melancholics "are afraid of light and avoid people, they are full of all sorts of dangers, complaining of abdominal pain, as if they are stabbed with thousands of needles.

Secondly, it is melancholy as a disease: "If the feeling of fear and cowardice continues too long, it indicates the onset of melancholy... Fear and sorrow, if they last a long time and are not caused by worldly reasons, come from black bile". He also described the symptoms characteristic of melancholia - food disgust, despondency, insomnia, irritability and anxiety. On the fact that the cause of the disease should be looked for in the human brain, guessed the predecessors of Hippocrates (Pythagoras and Alkmeon), but it was Hippocrates first recorded that "it is necessary to know that ... grief, sadness, discontent and complaints come from the brain ... It makes us crazy, we are enveloped in anxiety and fears either at night or as the day comes.

Aristotle (384-322 BC) asked a question that led, two thousand years later, to the creation of the rubric "Great Depressions or Great Depressions in Depression" as part of The question sounded as follows: "why were people brilliant in philosophy, or in government, or in poetry, or in art - why did they all seem to be melancholic? Some of them suffered from a spill of black bile, as, for example, among the Heroes - Hercules: it was believed that he was such a melancholic nature, and the ancient by his name, called the sacred disease Hercules. Yes, there is no doubt, and many other heroes, as is known, suffered from the same disease. And in later times also Empedocles, Socrates and Plato and many other wonderful men" (Problems XXX, I).

Plato (428-348 BC) in his works described the state of depression and mania. He described the state of mania as a disease of "right" frenzy originating from muses - it gives poetic inspiration and speaks about the advantage of the bearer of this disease over ordinary people with their worldly sanity.

Ancient Rome

But Mark Tullius Cicero (106-43 BC), a Roman orator, politician, and writer, came closest to the essence of melancholy in his "Conversations on Tusculapas". These lines, written more than two thousand years ago, describe the state of depression so accurately and clearly that many researchers believe that only a person who himself experienced a severe depression could have done so. Cicero wrote that "fear and sorrow come from thoughts of evil. It is fear that is the thought of the great evil to come, and sadness is the thought of the great evil already available and also fresh, from which naturally arises such a sadness that it seems to the tormented person that he is tormented by something. These excitement, as if some kind of fury lets human irrationality into our lives. He emphasizes that "any mental disorder is a disaster, grief or sadness like real torture. If fear causes depression, then grief lies in "exhaustion, marasmus, torment, crushing, distortion and, finally, the destruction, gnawing, destruction, destruction of the whole mind. He quotes the opinion of the Greek philosopher Chrysippius, who called the depression as if "corruption of man himself. Cicero mentions that in his time, many authors wrote about depression, including Homer, who said that in melancholy they often seek solitude. On the treatment of this condition, he writes that 'the body is treatable, there is no medicine for the soul.

Cicero said that it is often impossible to get out of a deep depression on our own: "It is not in our power to silence what is imagined by evil, to conceal or forget it. It chews, frightens, rattles, burns, keeps you from breathing, and you order to forget?" He mentions that the best cure since ancient times is time. At the same time, you can't rely only on time: "without removing it completely, you can't get rid of this disaster. He also notes that "the most important thing in consolation is to remove the perception of grief from the grieving person, as if he is doing a fair and proper duty. Cicero considered the best cure for melancholy to be conversations with the suffering person, that is, in modern language, he was one of the first to suggest the use of psychotherapeutic conversations to overcome depression. And of course, Cicero talks about the most important thing, the hope that a person "will endure the most severe suffering if, at least from a distance, he sees hope for something good.

Unlike Saul, who suffered from unexplained attacks of longing that modern medicine would characterize as endogenous depression, the depressive episode described by Plutarch (46-120 A.D.) can be characterized as psychogenic depression. The young Tsarevich Antioch suffered from severe depression, experiencing a pressing feeling of guilt, refusing to eat and dying right in front of his eyes. The court physician Erasystat suspected that the cause of melancholy was secret love. He put his hand on the heart of the young man, while all the women who lived in the palace took turns approaching him. When the young stepmother of the Tsarevich - the beautiful Stratonica - crossed the threshold, the young man's heart was beating, he shuddered and sweat drops appeared on his face. Erasystat reports the cause of illness to his father, and he is ready to give his wife and half of the kingdom, in order to rid his sons of black melancholy, which is about to bring him to his grave. This story served as a theme for the paintings of famous Italian artists Paolo Veronese and Berretini.

Avl Cornelius Cels, who lived in Rome in the 1st century A.D. during the Tiberius times, was not a doctor, but he made a huge encyclopedia for his descendants in all fields of knowledge of the ancient Romans, of which only medicine takes 8 volumes. "Melancholy is defined as a madness that takes a man for a long time, begins almost without fever, and then gives light fits last. This disease consists of sadness, which is apparently caused by a spill of black bile.

Roman doctor Asklepiad (128-56 BC) advised to treat melancholia with warm baths, moistening the head with cold water, laxatives, massage, moderate gymnastics, abstinence from fatty meat and wine, warning to leave a person in melancholia all alone and when there are improvements, advised to go on a trip.

Areteus of Cappadocia (second half of the 2nd century A.D.) in his treatises agreed with the ancients that "black bile, flooding the diaphragm, penetrating into the stomach, and causing there the gravity and swelling, the disorder of mental activity thus gives melancholy. But in addition, it can also occur in a purely mental way: some depressing performance, a sad thought causes a completely similar disorder. This is how it defines melancholy: "An oppressive state of mind that is focused on a thought. The sad idea itself can arise without any external causes, as it can be a consequence of an event. In his opinion, prolonged prolonged melancholy leads to indifference, complete dullness of the person who loses the ability to properly assess the situation.

Middle Ages

The great physician of the East Avicenna (980-1037) wrote that "melancholy is the avoidance of the natural path towards disorder, fear and spoilage. Melancholia is defined by excessive thoughtfulness, constant obsessions, and an invariably aspiring to one thing or to the ground". It is also indicated by sad expression, insomnia and thoughtfulness.

In the 11th century Constantine the African wrote a treatise "On Melancholy", in which he compiled data from Arab and Roman sources. He defines melancholia as a state in which a person believes in the advent of only adverse events. The cause of the disease is that the pairs of black bile rise to the brain, dimming the consciousness. This tendency is formed not by everyone, but only by persons with a special predisposition to it.

In Enagrius Pontiacus (346-399), John Cassian (360-435) described the pure, gratuitous melancholy of hermits who settled in desert areas. It overcomes these lonely people at noon, so it is called "noon demons". It is the main symptom of acedia (lethargy, laziness), which in the Middle Ages was synonymous with the old concept of "melancholy". The monk in the power of the acedia feels an overwhelming desire to leave his cell and seek healing elsewhere. He looks back furiously, hoping to see someone who goes to visit him. In his lonesome anxiety, he is threatened to fall into a state of apathy or, conversely, to flee furiously. Acedia, which for the hermits was a "indiscriminate attack that spoils at noon," was usually associated with Psalm 90. It paralyzed the ability to concentrate and pray. Enagrius Pontiac told his brothers that they should not give in to melancholy and leave their places.

Jean Francois Fernel (1497-1558), a Renaissance doctor, called melancholy a feverless madness. It occurs because of "brain exhaustion, weakening of basic abilities of the latter". Melancholia is a state when "the sick think and speak and act absurdly, they are long denied reason and logic, and it all goes with fear and despair. "Beginners" melancholiacs are sluggish, depressed, "weak in the soul, indifferent to themselves, life is considered a burden and frightened to leave it. When the disease develops, "with soul and mind, upset and disorderly, they imagine a lot, and this is almost all gloomy, others believe that they should not talk to anyone and they should spend their whole life in silence. They avoid society and people's attention, many are looking for loneliness, which drives them to wander among the graves, tombs, in wild caves. Well, quite a gloomy end - though, as in no way - the Middle Ages, a wild time.

Т. Bright (1550-1615) - The first English protopsychiatrist published in 1586 the first book on psychiatry in England. This book, consisting of 41 chapters, was entirely devoted to depression and was called "Treatise on Melancholy". According to some researchers, Bright was friends with Shakespeare. Moreover, analyzing and comparing the works of Shakespeare and the "Treatise on Melancholy", we can assume that Shakespeare was well acquainted with this work.

In England, melancholy was called "Elizabethan disease". Starting with Robert Burton's famous treatise "The Anatomy of Melancholy" (1621), praised by F. Engels, descriptions of melancholy as a mental illness are supplemented by a socio-psychological interpretation that emphasizes the importance of such factors as loneliness, fear, poverty, unrequited love, excessive religiosity, etc. Burton's words are interesting: 'I write about melancholy to avoid melancholy. Melancholy has no greater reason than idleness, and there is no better remedy against it than employment.

It is typical for the Middle Ages that all experiences are divided into vices and virtues. The Latin word desperatio ("desperation") meant not just a state of mind, but a vice, a sinful doubt in God's mercy. The acedia already mentioned, which meant apathy, spiritual laziness, carelessness, can also be attributed to this class. Often, the word tristitia ("sorrow") was used instead of Acedia. In the XIII century. this state began to be associated with the physical difference of bile and gradually the word acedia replaced the Hippocratic "melancholy" and began to be used in the meaning of "sadness. Medieval thought, thus, sees in apathy and instability of moods as both a vice and a disease (often both together).

Approximately the same is the fate of the French word ennui. Originally it was one of the derivatives of the word ennui, but Pascal already believes that fickleness, longing and anxiety are normal, albeit painful, human states. In the XVII century the word ennui denotes a very wide range of experiences: anxiety, oppression, sadness, longing, boredom, fatigue, disappointment. In the XVIII century. in the English dictionary of emotions appear the words bore, boredom ("longing", "boredom"), splee ("splee"). Times change, morals change - it becomes beautiful and fashionable to be bored and bored. Romanticists of the beginning of the XIX century. is already unthinkable without a sense of "world sorrow". What once was a mortal sin, worthy of condemnation, turned, as O. Huxley noted, first into a disease, and then into a subtle lyrical emotion, which became a source of inspiration for the authors of most works of modern literature.

Treatment of depression

Antidepressants, which are currently the most popular tool in the treatment of depression, were discovered only 50 years ago. But what about the depression was treated before?

In Ancient Rome, the treatment of melancholia "consisted of bloodletting, but if they are contraindicated because of the general weakness of the patient, they were replaced by vomit remedies; in addition, rubbing the whole body, movement and laxatives are necessary... In this case, it is very important to inspire the patient to cheer up, entertaining him with conversations on topics that were pleasant to him before" (A. Celsius). Patricia was also aware that "sleep deprivation along with entertainment" can temporarily relieve the symptoms of melancholy. This method was again undeservedly forgotten and discovered only in the second half of the 20th century (You can read a detailed article on the block "getting out of depression" about sleep deprivation).

In the 18th century in Germany, doctors tried to get rid of such a common symptom of melancholy, which was described by patients as "lead weight in the hands and feet", "powder weight on the shoulders" by a rather strange way. Patients were tied to swivel chairs and wheels, suggesting that centrifugal force could remove this weight.

In general, up to the 20th century, the patients who fell into the hands of psychiatrists were not very ceremonial. Hunger, beating, holding on a chain - this is a list of not the most brutal methods used in psychiatric institutions of that time. This is how even the English King George III was treated when he fell into madness - he was severely beaten on the advice of the best doctors in Europe. During one of the attacks, the king died. It should be noted that these methods "cured" mostly violent diseases, and because of depression patients behaved quietly, milder methods were applied to them.

For three quarters of the century, the medicine was dominated by the so-called hydrotherapy. To treat melancholia, they used a sudden immersion in cold water (so-called bainde surprise) before the first signs of strangulation, and the duration of these procedures was equal to the time required to not too quickly pronounce the psalm Miserere. The "popular" method of treatment was also struzbad: the melancholic was lying in the bath, tied up, and 10 to 50 buckets of cold water were poured over his head.

In Russia at the beginning of the 19th century, "vomit tartar, sweet mercury, whitewash, external rubbing of the head with vomit tartar, application of leeches to the anus, blistering plasters and other types of retardants were used to treat melancholia. Warm baths were prescribed in winter, and cold summers. Often put moxes to the head of both shoulders and share the burns on his hands.

Before the beginning of the drugs era, various narcotic substances were widely used. The most popular "antidepressant" was opium and various opiates, which continued to be used until the 1960s. The use of opium in the treatment of depression is mentioned in the treatises of the ancient Roman physician Galen (130 - 200 AD).

For the treatment of depression in the 19th century, the drug used was cannabis, which is in fact common marijuana or hemp. Cannabis has been used by mankind for more than 10,000 years. The first evidence of its use for pharmacological purposes, including depression, dates back to the 3rd century BC in China. Cannabis appeared in Europe much later - in the 19th century. In the 40s of the XIX century, the Parisian physician Jacques-Joseph Moreau de Toux believed that in order to get rid of melancholy it is necessary to "replace the symptoms of mental illness with similar but controlled symptoms caused by drugs" used cannabis in depression and found that it, among other things, causes revival and euphoria. This effect, however, was very short-lived.

In 1884, Z. Freud tried cocaine for the first time, which led to the release of his first major work, called "About Coca". It refers, among other things, to the use of cocaine in the treatment of depression. At the time, cocaine was sold freely and without prescription in pharmacies, and it took several years before the negative aspects of this "drug" - strong drug addiction - were uncovered, and that cocaine use in itself leads to depression, which was even called "cocaine sadness".


This section contains a classification of serotonin products and serotonin receptors - places where serotonin products are absorbed.

Classification of serotonin receptors

At present, about 15 types of central serotonin receptors are known. It has been found experimentally that neuroleptics bind mainly to serotonin (5-HT) receptors of the first three types. On 5-HT1a receptors these drugs have mainly stimulating (agonistic) effect. Probable clinical effects of this effect can be manifested in strengthening antipsychotic activity, reducing the severity of cognitive disorders, correction of negative symptomatology, antidepressant effect and reducing the number of extrapyramid side effects. The impact of neuroleptics on type 2 serotonin receptors, especially on subtypes a and s, is important. The 5-HT2a torus receptor is predominantly in the cerebral cortex and its sensitivity is increased in schizophrenic patients. Therefore, the blockage of 5-HT2a-receptors is associated with the ability of new-generation neuroleptics to reduce the severity of negative symptoms, improve cognitive functions, regulate sleep by increasing the total duration of slow wave (d-wave) stages of sleep, reduce aggression and reduce depressive symptoms and migraine-like (resulting from vascular disorders) headaches. On the other hand, with 5-HT2a-receptor blockage it is possible to increase hypotensive effects and ejaculation disorders in men. It is believed that the effect of neuroleptics on 5-HT2a-receptors causes a sedative (anxiolytic) effect, increased appetite (accompanied by increased body weight) and reduced production of prolactin. The 5-HT3 receptors are mainly located in the limbic region and in case of their blockage, the antiemetic effect develops first of all, as well as the antipsychotic and anxiolytic effect intensifies.

Classification of serotoninotropic drugs

A. Serotoninomimetics:

  • Indirect (presynaptic) action type - antidepressants: fluxetine, trasodone, fluvoxamine.
  • Direct (receptor-type action - adipine serotonin, mexamine, quipazine (used in experimental pharmacology).

B. Antiserotoninergic agents:

  • Indirect type of action:
    • Serotonin-disturbing - parachlorophenylalanine (used in the experiment);
    • interfering with serotonin-reserve deposit.
  • Direct (receptor) type of depression - serotonin receptor blockers:
    • specific competitive antagonists - methyzergide, pazotifen, lisuridium, ketanserine, ebrantil;
    • non-specific antagonists - ciproheptadine, aminazine, haloperidol, morphine;

Classification of antidepressants

  • Tricyclic (classic) antidepressants (TCA) and related compounds
    • Representatives: imipramine, dezipramine, amitriptyline, pyrazidol, lofepramine. Mechanism of action: non-selective suppression of HA and serotonin (5-HT) reverse capture by nerve endings of the corresponding brain structures, reversible inhibition of monoamine oxidase - MAO (pyrazidol).
  • Selective inhibitors of reverse capture of HA and serotonin
    • (SIOZNS) Representatives: venlafaxine, milnazipran. Mechanism of action: selective oppression of the NA reverse capture and serotoninan nerve endings
  • Selective Serotonin Retrieval Inhibitors (SIRCI)
    • Representatives: fluoxetine, paroxetine, sertralin, citalopram, clomipramine, etc. Mechanism of action: selective oppression of serotonin reverse capture by nerve endings
  • Monoamine oxidase inhibitors
    • irreversible. Representatives: phenelzine, trannylcypromine
    • reversible. Representatives: mochlobemide, pyrazidol
  • Serotonin Retrieval Activators
    • Representative: tianeptin (synonymous with coaxyl)
  • Antidepressants with receptor mechanism of action
    • Representatives: Mianserin - an antagonist of alpha2-adrenor receptors and Nafazodon 5-HT post-synaptic serotonin receptors - blocks post-synaptic serotonin receptors of 5-HT2 type, shows moderate affinity to serotonin membrane transporter. Mirtazapine - a) blocks presynaptic alpha2-adrenor receptors that inhibit serotonin release, resulting in increased serotonergic neurotransmission; b) blocks postsynaptic 5-HT2- and 5-HT3-receptors, resulting in modulation of serotonergic neurotransmission.

Mechanism of biological activity of antidepressants

Antidepressant washing mechanism

In the course of almost half a century of history of experimental and clinical study of antidepressants, the idea of their possible mechanisms of action has undergone significant evolution, characterized by several stages. As already noted, the first hypotheses explaining the antidepressant effect of imipramine and iproniazid proceeded from the idea of monoaminergic neurotransmission function impairment in specific brain structures responsible for regulation of the emotional sphere in depression conditions. It was found that inhibition of HA and serotonin backscrap, observed under the action of imipramine and dezipramine both in vitro and in vivo, is accompanied by an increase in synaptic action of these monoamines by increasing their extracellular concentration. A similar result is achieved in the conditions of inhibition of monoamine oxidase, because this slows down the metabolic degradation of neurotransmitters-monoamines, their intracellular content and presynaptic release increases. It is important to note, however, that the effect of inhibition of neurotransmitters backscatcher is already manifested with a single use of drugs, while it takes several weeks to achieve a clinical antidepressant effect. In addition, it is known that there are no correlations between the inhibitory (with respect to the function of back-up capture) concentrations of antidepressants and their average therapeutic doses in the clinic. In search of a molecular target for antidepressant action, specific high-affinity imipramine binding centers on brain membranes and platelets, called imipramine receptors, have been described. Later, it was shown that these sites represent a specific protein embedded in the presynaptic membrane of serotonergic neuron endings, the so-called membrane serotonin transporter, now described in detail by molecular biology methods. Thus, the ability of antidepressants to inhibit the reverse capture of neurotransmitters has been confirmed on the modern methodological level.

As can be seen, there are several molecular "targets" on the pre- and post-synaptic level, which are targeted by antidepressants. The presynaptic link of the adrenergic synapse is represented by: a) a membrane transporter providing a reverse capture of UA (shown by an arrow); b) an MAO enzyme localized in mitochondria; c) an alpha2-adrenorreceptor that performs inhibitory control of the presynaptic release of UA (respectively, blocking this receptor leads to increased neurotransmitter release, increased neurotransmission). Alpha1 and beta-adrenor receptors are localized on the post-synaptic membrane. The difference in the neurochemical organization of serotoninergic neuron is that at the presynapse level in addition to the specific 5-HT transporter (shown by the arrow) there are two types of receptors: serotonin autoreceptor 5-HT1A and adrenergic heteroreceptor alpha2, which provide double modulating control of serotonergic neurotransmission. Two types of adreno- (alpha1- and beta-) receptors and two types of serotonin receptors (5-HT1A and 5-HT2) are localized in the post-synaptic neuron.

The blockage of monoamine reverse capture is accompanied by the following synaptic balance changes:

  1. The extracellular concentration of monomoamines (HA and 5-HT) increases;
  2. alpha2- and beta-adrenorreceptor responses are depressed;
  3. responses of 5-HT1A and 5-HT2 receptors are decreasing;
  4. decreased sensitivity (desensitization) of alpha2-adrenor receptors will lead to increased HA and 5-HT release and corresponding changes in synaptic transmission;
  5. total post-synaptic information flow is weakened through beta-adrenal and 5-HT2 receptors, but enhanced by activation of alpha1- and 5-HT1A receptors.

It should be noted that in the above scheme, which reflects the complex nature of synaptic balance changes under antidepressant action, much remains unclear.

Similar reasoning is applied to the treatment of the mechanism of action of HA and 5-HT selective inhibitors with the difference that the latter do not bind to receptors (for some drugs the exception is muscarinic cholinoreceptor). Receptor-acting antidepressants, without affecting the reverse capture process, show their effects by blocking presynaptic alpha2-adrenor receptors, resulting in increased release of neurotransmitters (HA and 5-HT) into the synaptic space. Much attention has been paid in recent years to studying the mechanisms of antidepressant action. Research in this direction has led to a number of new ideas. The main contradiction for a long time remained the mismatch between the biochemical effect of a single ("acute") use of antidepressants and the result of prolonged administration of the same substances. It became obvious that the hypothesis of inhibition of monoamine reverse capture is not suitable as a neurochemical basis for a stable antidepressant effect observed in conditions of long-term antidepressant use. The notion of adaptive rearrangements of monoaminergic systems of the brain that develop in the course of long-term antidepressant therapy and include such links as regulation of receptor state, their coupling with secondary messengers, intracellular signal transmission, endocrine regulatory links, involvement of interleukin systems, E2 prostaglandin, and cyclooxygenase cascade has emerged. It has been shown that changes in these systems occur in depression and are subject to reduction during antidepressant therapy.

In the late 70's, the idea of desensitization of beta-adrenor receptors in the brain as one of the mechanisms of action of TCA emerged. This mechanism seems to be realized in conditions of persistent increase of extracellular concentration of HA. A state of lowered regulation of beta-adrenor receptors (the phenomenon of downregulation) is developing, in contrast to what happens in depression. A number of data suggests the possible involvement of other neurotransmitter systems, in particular, glutamatergic, steroid brain receptors, changes in secretion of growth hormone, involvement of hormones of the front end of the pituitary gland in the mechanisms underlying the antidepressant effect. These data, despite their fragmentariness, demonstrate the complexity of the problem under consideration, the solution of which, given its undoubted social significance, will require further multidisciplinary research.

  • Anticholinergic:
    • dry mouth, blurred vision, difficulty in urination, constipation, memory problems, exacerbation of corner glaucoma.
  • Antihistamines:
    • sedative effect, increase in body weight
  • Antagonism of alpha-adrenor receptors:
    • orthostatic hypotension
  • Cardiovascular effects:
    • sinus tachycardia, arrhythmias, myocardial conduction slowing down, sudden death
  • Others:
    • sexual dysfunction, cognitive and psychomotor disorders, convulsions

Mechanism of action according to the classification of antidepressants

Modern classification of antidepressants based on the peculiarities of their action mechanism, pharmacological and neurochemical profile, adopted in experimental and clinical psychopharmacology. Along with tricyclic (classical) antidepressants, drugs of different chemical structure are now widely used. Antidepressants of different groups with different chemical structure are characterized by different degree of selectivity of affinity to membrane transporters of monoamines - HA, serotonin, dopamine (DA), as well as to individual receptors. Quantitative characteristic of affinity (affinity) of a drug to this or that macromolecular complex, i.e. to a receptor or transport protein, is the value of IC50, which represents 50% of the inhibitory concentration of this substance. From the above data we can see that the group of classic antidepressants (TCA) is distinguished by significant heterogeneity of affinity to individual monoamine transporters. Thus, imipramine, having almost the same affinity to 5-NT and HA vectors, exhibits much less affinity to the YES capture system. Desipramine, like amitriptyline, has a higher affinity for the UA vector. The high degree of selectivity of chlorampramine (a close structural analogue of imipramine) in relation to the 5-HT capture process attracts attention. In essence, this drug can be considered as the first representative of the detention facility. The group as a whole has a characteristic low affinity for the YES carrier. Citalopramine and fluoxetine, as well as paroxetine and sertraline, belonging to the group of SEZ, are close to chlorampramine by activity and selectivity of affinity to the serotonin carrier. These substances have little effect on the reverse capture of catecholamines - HA and YES. Nomiphenzine and maprotyline, on the contrary, exhibit the properties of selective inhibitors of HA backscrapping. Let us consider pharmacological properties and features of neurochemical profile of the main groups of antidepressants consistently. First of all, it should be noted that despite the emergence of a large number of new drugs with a more selective effect of NA/serotonin backscrap, classical antidepressants imipramine and amitriptyline are still widely used in the treatment of depression, representing a kind of "gold standard". The main difference between classical TCAs is the relatively wide neurochemical profile, i.e. the ability to influence not only monomoamine capture but also central and peripheral cholino receptor-muscarin type, alpha-adrenal and histamine receptors. Most side effects of antidepressants (sedative effect, orthostatic hypotension, arrhythmogenic action, cardiotoxicity, accommodation disorder, dysuric disorders, etc.) are associated with this property. Antidepressants of the second generation, which include selective inhibitors of monoamine capture, have a narrower neurochemical profile, do not show affinity to most of the receptors and therefore are better transferred, they have less pronounced side effects noted above. At the same time, as extensive clinical studies have shown, new antidepressants are usually not superior to their classical first-generation predecessors in terms of therapeutic efficacy. The closest to the latter in terms of mechanism of action are drugs of SIOPNS group, selectively inhibiting the seizure of UA and serotonin in approximately the same concentration range and having no significant effect on other neurotransmitter systems. The representatives of this group are venlafaxine and milnazipran, which showed antidepressant effect in clinical trials. It is reported that the therapeutic effect of venlafaxine has occurred more rapidly during the first 2 weeks. Despite the apparent similarity of the neurochemical effect of NA/5-HT reverse capture inhibitors with the mechanism well known for imipramine type antidepressants, the difference between them lies in the lack of ability of the drugs of SIZNS group to cause desensitization of beta-adrenor receptors typical for the action of TCA.

Serotoninotropic substances

Serotonergic antidepressants (a group of SIZS) have been fully studied both in experimental conditions and in the clinic. Typical for these substances highly selective suppression of serotonin back capture is considered as one of the leading components of the antidepressant effect mechanism. A number of experimental proofs of serotonergic function strengthening under the action of these substances have been obtained. It has been shown, in particular, that at chronic, but not single administration of antidepressants of the IVSF group the increase of extracellular serotonin concentration in dialysates of the frontal cortex of rat brain is observed, that agrees with the notion of central serotonergic neurotransmission strengthening. The ability to inhibit serotonin backscatcher is manifested not only in vitro experiments, but also in vivo. It is interesting to note, however, that there are no correlations between these indicators and average therapeutic doses of the same antidepressants in clinical conditions. Thus, it is not difficult to see that fluoxetine, significantly inferior to paroxetine in its activity in the experiment, is equally effective under clinical conditions. On the whole, there is a greater correspondence of therapeutically effective doses in the clinic to the data of the experiments in vivo. Clomipramine is one order of magnitude more active than iipramine and amitriptyline, but the therapeutic effect of all three drugs is observed in the same dose range in the clinic. Fluoxetine, the most famous drug of this group, is characterized by a longer duration of action, as well as the ability to metabolize with the formation of pharmacologically activedezmethyl derivative. Period of half life of fluoxetine and its metabolite exceeds 7 days, which should be taken into account in case of drug withdrawal and transition to other therapy. MAO inhibitors, for example, can be used not earlier than 5 weeks after fluoxetine withdrawal. Paroxetine, one of the most powerful and selective inhibitors of serotonin capture, has recently been widely used. The drug causes adaptive changes in the state of somatodendrite (type 5-HT1A) and terminal (HT1B/1D) serotonin autoreceptors, inhibits the activity of NO-synthesis, an enzyme that catalyzes the formation of nitrogen oxide. Paroxetine is non-toxic, well tolerated and effective not only in depression but also in treating anxiety conditions. In the group of MAO inhibitors there are substances that show the ability to reversibly inhibit the activity of the enzyme - a domestic4-cyclic antidepressant pyrazidol, created in the Center for the Chemistry of Medicines VNICHFI, and moclobemide - a derivative of benzamide, which is close to the structure of xsupiride. Moclobemide is an inhibitor of the MAO-A isoform of the enzyme, its advantage over the inhibitors of phenelzine type is the possibility of its application simultaneously with food products containing tyrosine (absence of "cheese" effect). MAO-B inhibitors are not used in the therapy of depression. It remains unclear whether MAO-B inhibitors correspond to the reference TCA in terms of their therapeutic effectiveness in the treatment of depression. A special place among antidepressants is occupied by the tricyclic derivative of dibenzothiazepine thianeptin (synonymous with coaxyl), the mechanism of action of which is associated with the activation of serotonin backsliding processes, which in light of current data on the role of serotonergic deficit as a probable neurochemical basis for depressive states is a paradox. It is known that all clinically effective antidepressants increase the concentration of neurotransmitters, primarily serotonin, in the synaptic space by inhibiting their backsliding or slowing down metabolic degradation. In this sense, the purpose of antidepressant therapy is to enhance central serotonergic neurotransmission. Clinical efficacy of drugs from the group of SEEPS as a whole confirms the hypothesis of serotonin deficiency, as evidenced by the results of numerous studies. According to experimental data, tianeptin exhibits pharmacological properties typical for typical antidepressants. Clinical studies, including the results of European multicenter trials, indicate the efficacy of tianeptin, comparable with that of imipramine and amitriptyline. According to experimental data, serotonin capture amplification in cortical and hippocampal structures reached 28% with single and 71% with chronic administration of the drug. Similar data were obtained when a similar indicator was registered on platelets of patients treated with tianeptin. It was shown that thianeptin does not increase the extracellular serotonin concentration, but increases the level of DA in nucleus accumbens primi-microdialysis study and decreases the stress-induced increase of HA emissions in the frontal cortex. It is also known that the drug has an anxiolytic activity. The paradox is that the antidepressant effect of thianeptin is based on the effect on serotonergic neurotransmission parameters, which is directly opposite to that characteristic of the representatives of the group of detention centers. The originator of the new group of antidepressants is mainly receptor mechanism of action - mianserin, which is called atypical antidepressant due to its lack of noticeable influence on monome-amine back capture and ability to inhibit MAO. It turned out that mianserin, as well as its analogues mirtazapine and retyptyline (4-cyclic compounds with a pyrazidol-like structure), are blockers of alpha2-adrenor receptors localized by napresynaptic endings of adrenal and serotoninergic neurons. Receptors of this type perform inhibitory control over the release of neurotransmitters, i.e. HA and serotonin, and their blocking leads to the strengthening of neurotransmission in corresponding synapses. In in vitro and in vivo experiments, it was shown that myanserin causes an increase in the presynaptic release of HA and eliminates the effect of clonidine, an alpha2-adrenor receptor agonist. In addition, the drug inhibits the postsynaptic 5-HT2 serotonin receptors. Characteristic side effects of mianserin, such as orthostatic hypotension and sedative action, are associated with the effect of the drug on alpha1-adrenal and H1-histamine receptors of the brain. One of the new representatives of this group - naphasodone - along with the receptor effect has an affinity for the serotonin membrane transporter, which brings it closer to the substances of the group. Due to its depressing effect on post-synaptic 5-HT2 receptors, the drug has an anxiolytic effect, which determines the possibility of expanding the indications for its clinical use in the treatment of anxious depression. An interesting feature of naphasodone was its ability, unlike most antidepressants, to increase the proportion of fast sleep and have a normalizing effect on its structure, which is often disrupted by pre-depression. Another representative of antidepressants in this group - mirtazapine, an antagonist of presynaptic alpha-adrenor receptors - has, in addition, an oppressive effect on postsynaptic receptors such as 5-HT2 and 5-HT3. The cumulative effect can be determined by the functional ratio of facilitatory and oppressive effects in functionally heterogeneous serotonergic pathways. The high activity of antidepressants capable of selectively modulating the neurotransmission in brain serotonergic systems is well consistent with representations about the role of serotonin in the regulation of several important functions of the body.

Side effects of antidepressants are well known

As already noted, the advantage of new-generation antidepressants is low toxicity, significantly fewer side effects and better tolerability.

Clinical effects of antidepressants

The ability to influence the depth of the vitally altered effect is one of the most important properties of modern antidepressant. According to our data, in case of severe endogenous depression, the clinical effect of the SIEPS develops slightly slower (by the 4th week) than that of TCA, but by the end of the 2nd month of treatment they are leveled off in terms of the effect severity. It follows from this that it is not reasonable to cancel the SENS drug after a few weeks of treatment due to the lack of effect, as it should come a little later.

Another criterion for clinical use of antidepressants is the already classic P. Kilholtz scheme. According to this scheme, it is necessary to use antidepressants with stimulating effect in case of apathetic abulmic type depression, in case of anxious depression usually use drugs with anciolytic or sedative effect. Three main groups of drugs can be seen: stimulant, sedative and mixed effects. In this case, SIZS (except for fluoxetine) refers to drugs with balanced action. Paxil (paroxetine) belongs to them as well.

In our opinion, the most interesting for a clinician are the so-called atypical depressions, which, according to modern classifications, are characterized by the following features:

  • increased appetite up to hyperphagia;
  • increase in body weight;
  • hypersomnia;
  • situational-motivated character of the mood and its dysphoric connotation;
  • general weakness, lethargy;
  • hypersensitivity to situations of frustration;
  • inverse nature of the daily fluctuations in mood.

Another disorder - distimic - is of interest, because in this case the detention centers show high therapeutic effectiveness. Dystimic disorder is characterized by depressed mood for most of the day and the prevailing number of days according to subjective complaints or observations of others, lasting at least 2 years. During this period, 2 or more of the following symptoms are usually observed:

  1. reduced appetite or overeating;
  2. insomnia or hypersomnia;
  3. loss of energy or fatigue;
  4. low self-esteem;
  5. difficulties in concentrating and making decisions;
  6. feelings of hopelessness.

Such patients are very resistant to therapy. However, according to our data, in 53.8% of patients responded positively to the therapy of the isolation ward, while for TCA this figure was only 41.2%.

With a holistic approach to the treatment of depression as a chronic recursive disease, we can identify 3 main stages or phases of therapy:

  • curative therapy;
  • complementary or stabilizing therapy (6-9 months);
  • prophylactic (supportive) therapy.

Recurrence of disease in recurrent depression within 2 years after the end of active or stabilizing therapy develops in 50-75% of patients. Without pharmacoprophylaxis, 70-80% of patients who have had 3 depressive episodes or more within 3 years usually develop relapse. According to WHO, antidepressant treatment should be continued within 12 months after the disappearance of acute symptoms of depression.

Patients with relapses of depression during the last 5 years of the disease need preventive therapy. The question of discontinuation of thymoanaleptic therapy can be raised only after 2 years of euthentic period.

Speaking about the benefits of the isolation ward, it should be emphasized that, unlike TCA, they can be used more safely in patients with intercourse somatic diseases, such as:

  • prostate adenoma;
  • closed-angle glaucoma;
  • cardiovascular diseases;
  • obesity, etc.

SIZS can be more safely combined with other drugs (antihypertensive, b-blockers, antacids, antihistamines, oral contraceptives), other psychotropic drugs (neuroleptics, tranquilizers), and they also do not interact with tyramine and alcohol.

The indications for use of the SIZS are:

  • recurring depression (major depressive episode);
  • bipolar depression (in combination with thymoisoleptics);
  • dystemia;
  • obsessive-compulsive disorder.

According to preliminary data, the relative indications for the treatment of the SIZS are:

  • panic disorder;
  • bulimia;
  • social phobia;
  • alcoholism and other substance abuse;
  • chronic pain syndromes;
  • mixed anxiety and depression states;
  • somatoform disorders.

Methods of obtaining some serotoninotropic


Synonyms: Crystoserpin, Rannorin, Resercen, Residin, Serpasil and others.

Rezerpin is the main alkaloid of the plant rauvolphia sem. Arosupaseaea, which grows in tropical and subtropical areas. More than 50 alkaloids belonging to the groups of derivatives of iohimbana (I), 6-iohimbana (II), indolin (III) and isoquinolin have been isolated from different types of rauvolphia; in total, the plant contains up to 2% of alkaloids, of which the share of reserve and restsinamine (IV) is 0.04-0.18%:

The five-cyclic nucleus is known as epileiochimbana. In the reservine molecule, atoms C3, C15, C16, C17, C18 and C20 are asymmetric.

The reserve is extracted from the roots of the plant by extraction of ammonia in the presence of ether; after removal of most of the solvent (ether), the residue is extracted with aqueous tartaric acid solution, washed with petroleic ether, alkaloids are dissolved in the chloroform and passed through the chromatographic column filled with aluminum oxide. Washing out of the column is done with chloroform, dichloroethane or other organic solvents.

Д. G. Kolesnikov and his staff established the expediency of extracting the alkaloids of rawolfia with 10% acetic acid. The synthesis of reserve was carried out in 1956 by Woodward with his employees.

6-Methoxytryptamine (V) is condensed with 5-methoxy-4-acetoxy-6-methyl ether-2-aldehydocyclohexandicarboxylic acid 1.6 (VI) and the resulting azolactam (VII) is cyclized. At interaction (VIII) with phosphorus chloride the formation of methyl acetyl reserpate chloride (IX) takes place and at subsequent recovery - the formation of methyl acetyl acetyl isoreserpate (X). After conversion of isoreserpic acid lactone (XI) into reserve acid lactone (XII), the latter is converted with trimethoxybenzoyl chloride (XIII) into a mixture of d, l-reserpine (XIV).

Other ways of synthesis are described in detail by L. Yakhontov in the journal "Success of Chemistry" for 1957.

Reserpine is a white or yellowish crystalline powder, t. p. 261-265° (with separation), [a]D from -113 to -122° (with=1; chloroform), easily soluble in chloroform, little soluble in water, alcohol and ether at 295 mmc. Solution in concentration 0.4-2 mg per 100 ml chloroform

To obtain the reserve hydrochloride, the latter is treated with the calculated amount of hydrogen chloride alcohol solution. Rezerpine is easily inactivated in acidic and alkaline environment. Due to this, reserve agents do not sterilize.

Rezerpin gives a number of colored reactions with molybdenum acid (yellow coloring, turning into blue), with vanillin solution in hydrochloric acid (pink), with dimethylaminobenzaldehyde in the presence of ice acetic and sulfuric acids (green, turning into red), with sulfuric acid in the presence of sodium nitrite (green fluorescence).

The purity of the drug is determined by the absence of impurities (sulfates).

Reserve quantification is performed by acidimetric titration of its solution in anhydrous acetic acid with 0.1 n. chloric acid solution in anhydrous acetic acid, in the presence of an indicator of crystalline violet to green staining. 1 ml of 0.1 n. chloric acid solution corresponds to 0.06087 g of reserve, which should be not less than 98.5% and not more than 101.5% in the preparation.

Stored under lock (list A), in well-corked jars of orange glass, in a cool, protected from light place.

The highest single dose is 0.001 g, daily - 0.005 g. It is used to treat hypertension and mental illness of 0.1-0.3 mg per day after meals. The course of treatment is 1.5-4 months. Children under the age of 1 year - 0.1 mg 1-2 times a day, up to 5 years - 0.1 mg 2 times a day and from 6 to 12 years - 0.1 mg 2-3 times a day.

Serotonin adipine

White or white with a creamy tint of crystalline powder, odorless, soluble in water, difficult to dissolve in alcohol, insoluble on the air, t. Sl. 175 - 179 ° C (in the range of 2 ° C); MRTU 42 № 3851-70.

Serotonin - biogenic amine, which has a variety of physiological properties. Its characteristic feature is the ability to cause the reduction of smooth muscle and narrowing blood vessels, shorten bleeding time, increase the number of platelets in the peripheral blood and their aggregation, increase the stability of capillaries.

Serotonin adipinate is used to treat hemorrhagic syndrome in various pathological conditions, including Werlhof disease, hypo - and ap-lastic anemia, thrombasthenia, hemorrhagic va-sculitis, after the treatment of malignant tumors with cytostatic agents.

It is produced in 1 ml 1% N solution in ampoules. 10.

The method for the synthesis of adipine serotonin has been developed in VNIHFI based on the scheme proposed by Abramovich and Shapiro.

The scheme is similar to the production of mexamine and provides for the use of a common semi-product - potassium salt Z-carboxypipiperidone-2 (V), the method of preparation of which from low new ether and acrylonitrile is considered in the presentation of the method of synthesis of mexamine.

Paranitrophenol (I) in the interaction with benzyl chloride in an alcohol-alkaline medium is converted into p-benzyl zyloxynitrobenzene (II), which is reduced in the presence of nickel catalyst to p-benzyloxyanily-na (III), and the last diazotize sodium nitrite in a hydrochloric acid medium. The obtained p-p-p-penzyloxyphenyldiazonium chloride (IV) without extraction is subjected to interaction with potassium salt Z-carboxypiperidone-2 (V). The resulting p-p-p-penzyloxyphenylhydrazone piperidindio-na-2,3 (VI) is cycled through Fischer in the presence of sulfuric acid. The product of cyclization-1-oxo-6-benziloxy-1,2,3,4-tetrahydro-r-carboline (VII) is washed with caustic potassium with the opening of the lactate ring and during further processing with acetic acid 5-benziloxy-trypttamine-2-carbonic acid (VIII) is released. To avoid re-closing of the lactate cycle, phthalylic protection of the primary amino group is performed and N-phthalyl-5-benziloxytryptamine-2-carboxylic acid is thermally decarboxyled to M-phthalyl-5-benziloxytryptamine (IX). In compound IX, the removal of M-phthalyl alcohol protection is carried out by hydrazine hydrazine hydrazine, O-benzene protection by hydrogenation in the presence of palladium catalyst. The resulting serotonin is isolated in the form of adipinate XI. This method is superior to other methods of serotonin synthesis described in literature: from m-nitrobenzaldehyde through m-oxybenzaldehyde, 2-nitro-5-oxybenzaldehyde, 2-nitro-5-benziloxy-β-nitrosterol and 5-benziloxyindol with subsequent condensation with oxalyl chloride, treatment with dibenzylamine, reduction of lithium aluminahydride and catalytic removal of O-gas protection (And stages with a total yield of 11%); from o-chlorobenzoic acid through 2-chloro-5-nitrobenzoic acid, 2-chloro-5-aminobenzoic acid, 2-Carboxyme-til-M-acetylamino-5-benziloxybenzoic acid, 1-acetyl-Z-acetyl-5-benziloxyindol, 1 -acetyl-5-benziloxy-indoxyl with subsequent condensation with cyanacetic acid, the reduction of nitrile group of lithium alumina-ride and catalytic removal of p-gas protection (11 stages with a total yield of 11%); by Fischer reaction from p-benzyloxyphenylhydrazine and hard-to-reach acetal γ-amino-oil aldehyde, from diethyl aether of succinic acid and ethylformate through β-formyl-propionic acid and its p-benzyloxyphenylhydrazone with the Fischer reaction, transformation of 3-carbeto-xymethyl-5-benziloxyldol through hydrazide into amide and restoration of the last lithium aluminide (8 stages with a total yield of 10.5%); from p-penzyloxyaniline through p-penzyloxyphenyldiazonium chloride and the product of interaction of the latter with ethyl ether of a-acetyl-b-phthalimy-dovalerian acid with further cyclization along Fisher and removal of N-phthalyl and O-benzyl protective groups (nine stages with a total yield of ~11%).

p-Benzyloxynitrobenzene (II)

Mixture of 252 g of p-nitrope-nol (I), 1.92 liters, isopropyl alcohol, 134 ml 42% solution of caustic soda and 250 ml of benzyl chloride boil for 6 hours, cool to 15 ° C and leave at this temperature for 2 hours. Sludge II is filtered and washed with isopropyl alcohol (2 times 120 ml) and water (3 times 500 ml). They receive 387.7 g (93%) II with t. p. 106-107 ° C (content of the main substance is 99%).

p-Benziloxyaniline hydrochloride (III)

Solution 840 g II in 4.2 liters of ethyl alcohol hydrogenated in the presence of nickel catalyst at 20-25 ° C and a pressure of 20 atm. The catalyst is filtered out and 500 ml of ethyl alcohol is washed. To combined alcohol solutions at a temperature no higher than 16 ° C is poured gradually with stirring ~ 400 ml of hydrochloric acid to pH 3.5. III crystals are separated; for complete crystallization they are given 1.5 h at +5°C, checking pH periodically. The sediment is filtered out. Alcohol is evaporated to Vis initial volume, the rest is cooled to 10-15 ° C and additionally allocated amount 111 is filtered. General yield 786 g (91%); t. pl. 214-216 ° C, the content of the main substance is not less than 99%.

3-p-Benzyloxyphenylhydrazone piperidindione-2,3 (VI)

In the mixture 900 ml of water and 195 ml of hydrochloric acid dissolve 141.4 g III. The solution is cooled down to 10-15 ° C and a solution of 46.3 g of sodium nitrite is gradually poured into the PO ml of water under the surface, maintaining the temperature of the reaction mass of 10-15 ° C due to external cooling. Give an additional 30 minutes of exposure and control the end of the reaction with iodine starch paper (in the presence of free nitric acid). Nitric acid is decomposed by adding 5 g urea. A solution of 140 g of sodium acetate in 140 ml of water is poured to the diasor solution to pH 4.5-5. The mass is cooled to 0°C, filtered and when stirred, added to the cooled to 0°C and acidified acetic acid to pH 4.5-5 solution V prepared, as described in the synthesis of mexamine (see p. 164), from 105.8 g Z-carbethoxypiperidone-2. External cooling is removed and the mass is stirred for 6 hours (the temperature gradually increases to room temperature), after which the stirring continues for another 24 hours at 20-25 ° C. Sediment VI is filtered out, washed with water (5 times 100 ml), alcohol (2 times 50 ml) and dried in a vacuum at 40 ° C. Output is 177.8 g (86.9%).

1-oxo-6-benziloxy-1,2,3,4-tetrahydro-r-carboline (VII)

Mixture of 540 ml of ethyl alcohol, 27.6 ml of sulfuric acid and 177.8 g of hydrazon VI boil when stirring 2 hours. When heated, the suspension of hydrazon VI dissolves and after about 1 hour sludge VII appears. The mass is cooled to 8-10 ° C for 2 hours. Sediment VII is filtered out, 60 ml of ethyl alcohol is washed and 3 times 100 ml of labor (until there is no acidic reaction to congo). They receive 190 g of raw VII (127 g in terms of dry, yield 80.7%), which without drying is sent to the next stage.

5-Benzyloxytryptamine-2-carboxylic acid (VIII)

To a solution of 216 g of caustic potash in 1.3 liters of water add 100 g of carboline VII (in terms of dry) of 1.3 liters of ethyl alcohol. Boil when stirring for 6 hours, acidify with acetic acid (~ 216 ml) to pH 6, cool to 20-30 SS, give 1 hour exposure. Sediment is filtered, washed with 200 ml of 50% ethyl alcohol and 5 times 200 ml of hot water. Dry at 1000 C. The sediment is filtered, washed with 200 ml of ethyl alcohol and 5 times 200 ml of hot water. Yield 122 g (86.5%); t. pl. 212-214 ° C, the content of the main substance is at least 86%.

5-Benzyloxytryptamine (X)

Mix 100 g of finely crushed acid VIII with 50.2 g of phthalic anhydride and heat without stirring to 180 ° C. At the same time, M-phthalyl-5-benzyloxytryptamine-2-carboxylic acid is formed and water is distilled. Then the temperature is gradually raised for 1 h to 240 ° C. The process of decarboxylation begins and the mass is liquefied. Let the stirrer and stirring at 235-240 ° C continue for 2 hours (end of decarboxylation controlled after the end of the release of carbon dioxide). Then the mass is cooled down to 100 ° C and gradually added 700 ml of ethyl alcohol and 45 ml of hydrazine hydrate. Boil when stirring for 3 hours, cooled to 20 ° C, the sediment is filtered and washed with alcohol (3 times 50 ml). Combined alcohol solutions are cooled to 5 ° C and acidified with hydrochloric acid (~65 ml), stirring at 0 + 5 ° C continues for 3 hours. The released sediment of 5-benzyloxytryptamine hydrochloride is filtered, washed 2 times with 25 ml of ethyl alcohol and dissolved in 1.2 liters of boiling water with the addition of 8 g of coal. To filtered aqueous solution at 70-80 ° C and stirring is gradually poured 10% solution of caustic soda - to a stable strong alkaline reaction of phenolphthalein. The mass is cooled down to 10 ° C, the released sediment of the base X is filtered, washed with water (3 times 20 ml) until there is no alkaline reaction and dried at 50 - 60 ° C, after which it is recrystallized from 200 ml of benzene with the addition of 2 g of activated carbon. The X crystals, which fell out when cooled to 10 ° C, are filtered out and washed 2 times with 20 ml of cold benzene. Benzene filtrates are evaporated to 0.2 of initial volume, cooled to 10 ° C and filtered with additional X. Total yield is 27.5 g (37.7%); t. pl. 90 - 92 ° C; content of the main substance is not less than 98%.

Serotonin adipinate (XI)

150 g X, 3 liters of ethyl alcohol and 30 g of palladium catalyst containing 5% palladium oxide on potassium carbonate, hydrogenated at 18-25 ° C and a pressure of 3 atm. The catalyst is filtered out, 150 ml of ethyl alcohol is washed and a hot solution of 82.5 g of adipic acid is poured into the alcohol filtrate; \в 450 ml of ethyl alcohol. (Filtration of solutions containing serotonin and production of adipine serotonin should be done quickly, because serotonin in the air gets darker). During cooling, a sediment of adipine serotonin is released (the release of crystals is accelerated by inoculation). The mass is cooled for 1 hour at 0 ° C, the product is filtered and washed with 150 ml of ethyl alcohol. Alcohol uterine solutions are evaporated in vacuum to '/in the initial volume and release additional XI. All the resulting product is recrystallized from 85% ethyl alcohol with the addition of activated carbon. Alcohol solution is cooled to 0 ° C, XI filtered, washed with cold (0 ° C) ethyl alcohol and dried at 50-60 ° C. Received 143 g (82.4%) XI.


When condensed according to Michael malonewood ether (I) with acrylonitrile (II), the diethyl ether of β-cyane-ethylmalonic acid (III) is obtained, which is transformed into 3-carbethoxypiperidone-2 (IV) by catalytic reduction in the presence of nickel. The etheric group in oxoether IV is washed and the resulting potassium salt of Z-carboxypiperidone-2 (V) is subjected to interaction with p-methoxyphenyldiazonium chloride (VI), formed by diazotization of sodium nitrite in the hydrochloric acid medium of p-anisidine (VII) without extraction. The resulting 3-methoxyphenylhydrazone of piperidindione-2,3 (VIII) is subjected to cyclization by heating in an aqueous-alcoholic medium with an acid catalyst. Fisher cyclization product - 1 -oxo-6-methoxy-1, 2, 3, 4-tetrahydro-β-carboline (IX) - is washed with caustic potassium with the opening of the six-segmented lactate ring and 5-methoxytryptamine-2-carbonic acid (X) is released during further acetic acid treatment, which is subjected to decarboxylyrovaniya with further extraction of 5-methoxytryptamine hydrochloride [mexamine (XI)]. The above method has an advantage over other methods of synthesis of 5-methoxytryptamine published in the literature: from p-methoxyphenylhydrazine and diethylacetal γ-amino oil aldehyde with cyclization by Fisher of the corresponding hydrazon based on the use of hard-to-reach - γ-amino oil aldehyde; from p-methoxyphenylhydrazine and hard-to-access γ-chloro-oil aldehyde, from 5-methoxyindol through a magic-organic derivative with further condensation with chloroacetony-tril and reduction of 5-methoxyindoly-Z-acetony-tril in boiling alcohol; through the Wilsmeyer reaction 5-methoxyindoly-Z-aldehyde and 3-(β-nitrovinyl) -5-methoxyindol with the reduction of the last lithium alumogyloide in tetrahydrofuran; from p-methoxyphenylhydrazone β-forformylpropionic acid by cycling through Fisher into the ethyl ether of 5-methoxyindolyl 3-acetic acid and further through hydrazide and amide with the reduction of the last lithium alumohydride; from p-methoxyphenyldiazonium chloride and ethyl ether of α-acetyl-b-phthalimidovalerian acid with cyclization of the resulting Fischer hydrazon (in the variant of Abramovich and Shapiro), saponification of ester group in 2-carbethoxy-3-(β-phthalimidoethyl)-5-methoxyindol, decarboxylation and removal of phthalyl protection; from 5-methoxyindol through 5-methoxygramin and 5-methoxyindolyl acetonitrile with the reduction of the nitrile group by method A. P. Terentyev, M. N. Preobrazhenskaya and Ban-Lun-Ge - by the action of hydrazine hydrate in the presence of Reney nickel.

Diethyl ether of β-cyanethylmalonic acid (III)

To 1137 ml I add 47.2 g of sodium. When he fully reacts, the mass is heated to 80 ° C and 496 ml II is tapped at such a rate that the temperature remains within 85-90 ° C. Mix until the temperature drops to 70 ° C, and cool to 20 ° C. Then add 20 ml of 98% acetic acid (pH reaches 5-6), stir for 15 minutes, check the pH of the solution, add 680 ml of dichloroethane and 480 ml of water. Sodium acetate and by-products of acrylonitrile polymerization are transferred into water solution. Dichloroethane layer is separated, washed with water 2 times 200 ml and evaporated at a pressure of 100-150 mm Hg. The rest is distilled in a vacuum, the fraction with t. bale is collected. 164-168 ° C (8 mm Hg). Output 1002 g (65.5%), counting on II.

3-Carboethoxypiperidone-2 (IV)

The solution of 1 kg of cyanephi-ra III in 800 ml of absolute ethyl alcohol is hydrogenated in the presence of 75 g of nickel catalyst at 50 ° C and the pressure of 50-60 atm. The end of hydrogenation is determined by the method of HCG, analysis of the selected sample (content of III should not exceed 2%). The catalyst is filtered out. Volatile amines formed as by-products of hydrogenation are separated from filtrate by nitrogen blowing within 6 hours and may cause strong foaming without blowing off during subsequent evaporation. Then distillation of alcohol (for more complete removal of alcohol, preventing further recrystallization from freon-113, at the end of distillation connect a vacuum with a residual pressure of 150 - 200 mm Hg and raise the temperature in a mass up to 90-95 ° C). The residue is recrystallized from 1000 ml of CFC-113 [the substance is dissolved at 45-47°C, crystallized at 0-(+3°C)]. The sediment is filtered out, washed with 200 ml of CFC-113 and dried in vacuum. Output is 443 g (55.5%).

3-P-Methoxyphenylhydrazone piperidindione-2.3 (VIII)

To the solution of 94 g of caustic potassium in 2.5 liters of water added 251 g IV, heated for 3 hours at 27-30 ° C with mixing and to cooled to -5 ° C solution of potassium salt Z-carboxypipiperidone-2 (V) is poured cooled to -2 ° C aqueous solution of p-methoxyphenyldiazonium chloride, prepared by diazotization of 196 g recrystallized from ethyl alcohol p-anisidine (VII) [diazotization is carried out by gradual addition to VII, dissolved in a mixture of 1.85 l of water and 706 ml 27% hydrochloric acid, 485 ml of sodium nitrite solution containing 20 g / l of the main substance, maintaining the pH solution of 1.0, temperature - 2 - (+2 ° C) and controlling the end of the process on iodine paper; excess sodium nitrite is decomposed by tapping 50% of the solution of urea at the same temperature until a negative reaction to nitrite ion on the iodine starch paper, then the excess hydrochloric acid is neutralized by a solution of potash to pH 6.0]. The interaction of VI with V is carried out in acetic acid at pH 4.0, for which within 2-3 minutes to the reaction mixture of 2.13 liters of acetic acid at a temperature no higher than +2 ° C. To complete the reaction mass is stirred 30 h at - 2-(+2°C) and 24 h at 0°C-(+4°C). Sediment VIII is filtered out, washed with water (2 times 250 ml) and dried at 20-25 ° C in vacuum. Output 288 g (86%, counting on IV).

1 -Oxo-6-methoxy-1,2,3,4-tetrahydro-β-carboline (IX)

To 1.24 l 50% of ethyl alcohol added acid catalyst and 295 g 3-p-methoxyphenylhydrazone piperidinon-2.3 (VIII) and boiled for 3 h, cooled to 0- (+3 ° C), stirred at this temperature for another 2 h (a decrease in temperature below 0 ° C leads to contamination of the crystallizing product with resinous impurities). Sediment IX is filtered out, washed with water to neutral reaction (consumed ~ 1.68 liters of water) and dried in a vacuum at 60-70 ° C. Output is 192.5 g (70%).

5-Methoxytryptamine-2-carboxylic acid (X)

To a solution of 119 g of caustic potassium in 950 ml 60% of ethyl alcohol is added 61.5 g IX and the mass boiled for 8 hours, then distilled part of the ethyl alcohol, raising the temperature in pairs to 95 ° C for 3 hours. To the residue is poured 100 ml of water, add 12 g of coal and stir 15 minutes at 30-35 ° C, coal is filtered and filtrate cooled to 8-10 ° C, slowly pour 96% acetic acid to pH 6 at such a rate that the temperature of the reaction mass does not exceed 15 ° C. Then, the mass is cooled to 0 ° C and give 5 hours of exposure. The released sediment X is filtered out, washed with 50 ml of water and used as a paste containing 32% of the main substance, 14% potassium acetate and about 54% water at the next stage.

5-Methoxytryptamine hydrochloride (mexamine) (XI)

The paste X obtained in the previous stage is mixed with 442 ml of water and 102 ml of 28% hydrochloric acid. Slowly heated until boiling (foaming due to carbon dioxide emission takes place). When the mass boils, the current of carbon dioxide is strongly slowed down and in order to complete the process and protect against oxidation of oxygen in the reaction mass through the barbathere begins to pass nitrogen. Boiling in a current of nitrogen continues for 4 hours, then the mass is cooled to 40-50 ° C, bleached with coal and treated at 25-35 ° C 150 ml 42% solution of caustic soda, cooled to 0-(+5 ° C) and give 2 hours of exposure. The released base sediment 5-methoxytryptamine is filtered out, washed with 30 ml of cold (10 to 12 ° C) water, dried and dissolved in 1.8 liters of methylene chloride. The solution is dried with calcined potash, diluted with 40 ml of absolute ethyl alcohol and purified by passing through a "carbon cushion" prepared from 80 g of neutral activated carbon washed with methylene chloride and ethyl alcohol. 30% hydrogen chloride solution in ethyl alcohol is added to the filtrate up to pH 4-5. Silt XI is filtered out, washed with a mixture of methylene chloride and ethyl alcohol (45:1), dried at 20-22 ° C and a residual pressure of 300 - 400 mm and recrystallized from absolute ethyl alcohol in a ratio of 1:20 with the addition of 2.5% neutral activated carbon. The process is carried out in a nitrogen atmosphere. Output XI (taking into account the separated from uterine solutions) is 22.1 g (34.4% on IX).

Dibenzazepine antidepressants

Seven-membered cycles with one or two cyclic heteroatoms are an integral part of pharmacologically valuable compounds. Thus, the derivatives of azepine (a seven-membered heterocycle containing one cyclic nitrogen atom) are known as antidepressants. Substituted thiepins (a seven-membered cycle with a cyclic sulfur atom) have proven to be interesting as anesthetics, hypotensive and antihistamines. Compounds of 1,4-diazepine series (including two cyclic nitrogen atoms) have tranquilizer properties. Among thiazepines (a heterocycle contains one sulfur atom and one nitrogen atom), hypotensive agents were found. A number of dihydro-derivatives dibenzo(b,f)-azepines have entered into medical practice due to their strongly pronounced ability to relieve depressive states of mental disorders. Typical representatives of this class of antidepressants are dezipramine (1), imipramine (imizin, 2) and other drugs (3,4). They all have an aminopropyl group with different substituents in a cyclic nitrogen atom. It was found that some of these drugs relieve depression by inhibiting the reverse capture of mediator monoamines by neuron:

Below is a scheme for the synthesis of dezipramine (1) and lofe-pramine (3), which begins with the formation of the seven-membered dihydroazepine cycle (compound 7) by intramolecular electrophilic condensation of diarylamine (6), obtained from amine (5). After restoration of carbonyl group to me-tylene, N-alkylation of diazepine (8) with 3-chloropropanol is performed. In the resulting alcohol (9) is replaced by OH-group for chlorine, and then the methylamine group is introduced, thus synthesizing dezipramine (1). N-Alkylation with l-chlorophen-acylbromide is followed by another antidepressant - lofepramine (3).

Sometimes, replacing the azepine fragment with cycloheptane does not lead to loss of antidepressant properties (compare the structure of imipramine and amitriptyline (10).

It should be noted that the antidepressant (10) (amitriptyline, tryptizol) contains a biphenylmethylene fragment, which brings it closer to the pharmacological block of drugs that have in their structure a "magic group" of biphenylmethane derivatives. This structural similarity is to some extent confirmed by the noticeable sedative and cholinolytic action appearing in tryptizol (10).

Synthesis and study of phthalimidoalkylpiperazines

The discovery in the late 1980s of the important role of 5-HT1A receptors in the pathogenesis of anxiety and depression stimulated the active search for their ligands. Among the compounds with high affinity for 5-HT1AR, the most studied are derivatives of aryl(getaryl) piperazines with an anxiolytic effect, although only buspiron and hepiron, which are partial agonists of 5-HT1A receptors, have been introduced into medical practice so far.

The main factors limiting their use in the clinic are low bioavailability, delayed therapeutic effect (sometimes after 2-6 weeks, high affinity of these compounds to adrenaline (α1, α2, β2), dopamine (D2) and some other CNS receptors.

The reason for low selectivity of aryl(getaryl)piperazines is the "evolutionary" proximity of 5-HT1A-serotonin, D2-dopamine and α1 adrenaline receptors belonging to the same superfamily of G-protein conjugate receptors. The analysis of primary amino acid sequences indicates a high degree of their homologation(1). However, the detection of such highly selective ligands of 5-HT1A receptors as (SJ-UH-301 and WAY-100635 [II]) indicates significant differences in the binding centers of these receptors. Search and identification of structural features of buspiron analogues influencing selectivity to 5-HT1A-receptors are important not only for the synthesis of potential drugs with selective therapeutic effect but also for studying the features of ligand-receptor interactions.

The aim of this study is to synthesize phthalimidoalkylpiperazines that differ in the length of the polymethylene spacer, structure of the aryl fragment, and to study their affinity to the 5-NT1A-serotonin, D2-dopamine receptors of the rat brain, as well as their anxiolytic properties.

Hydrobromides of 4-(phthalimidoalkyl)-1-arylpiperazines (I, t = 1) were synthesized by the action of co-bromalkylphthalimides II on 1-arylpiperazine III in the alcohol medium (butanol or pentanol) or acetonitrile. The bases 1a - d (t = 0) were obtained by the same scheme, but in the presence of soda or potash. ω -5-Bromalkylphthalimides II (n = 2 - 6) were obtained by boiling.

A mixture of 3.082 g (11.5 mmol) 2-(3-brompropyl-1)-phthalimide, 1.06 g (10 mmol) Na2CO3 1.517 ml (10 mmol) of 1-phenylpiperazine and 15 ml of anhydrous acetonitrile boiled for 6 hours, cooled and diluted with water (40 ml). Filter the sediment and recrys-tallize it from benzene. They receive 2.55 g of substances in the form of yellow crystals.

Compounds 1a, b, g were synthesized in the presence of potash under the conditions described earlier.

Hydrobromide 1-{2-chlorophenyl)-4-[6-(phthalimido)-hexyl]piperazine (1p). Mixture of 1 g (5 mmol) of 1-(2-chlorophenyl)piperazine, 1.5 g (5 mmol) of 6-phthalimido-hexyl bromide in 10 ml of pentanol boiled 24h and cooled. Sediment is filtered out, washed with acetone, ether and recrystallized from ethanol. Output 0.57 g, in close conditions receive compounds 1d - n, c-f.

Results and their discussion

Radioligand analysis data indicate that compounds containing 1- or 2-link bridge are characterized by almost complete absence of affinity to both 5-NT1A-serotonin and D2-dopamine CNS receptors. Compound 1c, containing propylene bridge, has a submicromolar affinity for 5-NT1A-serotonin receptors. The lengthening of the propylene bridge by one carbon atom leads to the production of high-affinity compound Ig, and the affinity of this compound is 18.6 times higher to 5-NT1A-serotonin receptors than to D2-dopamine receptors. The introduction of ortho-C1 substituent into the arylic fragment (compound 1d) increases affinity to 5-NT1A-serotonins and decreases to D2-dopamine receptors. It should be noted that all opmo-Cl phenyl derivatives of phthalimido-piperazines, regardless of the number of methylene groups in the alkyl chain, show high affinity for 5-NT1A-serotonin receptors (Ki compounds vary in the range of 5.2-14 nM).

Replacement of the chlorine atom by the methyl group in the aromatic fragment leads to a significant decrease in affinity to 5-NT1A-serotonin (1e) and D2-dopamine (1j) receptors. Introduction of the methyl group into meta- or para-position or simultaneous introduction of two methyl groups into positions 2 and 4, or 2, and 5 of the aryl fragment of the 4-phenyl alkylpiperazinyl phthalimide molecule significantly reduces the efficiency of their binding to both types of receptors.

The increase in the length of the polymethylene bridge (n > 4) noticeably worsens the binding to D2-dopamine receptors, making these compounds more selective to 5-NT1A-serotonin receptors.

Compound 1m binds almost 100 times more selectively to 5-NT1A serotonins than to D2-dopamine receptors.

Compound 1m has an anxiolytic activity and is as effective as buspiron.

As follows from the data, there is a reliable dependence between affinity and anxiolytic activity of the studied compounds (R = 0.92).

The data obtained can be used to search for new potential anxiolytics among selective ligands of 5-NT1A serotonin receptors.

By: Alexandra Dimant

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