Poisoning by psychotropic drugs, not elsewhere classified: clinical guidelines

List of Abbreviations

Terms and Definitions

Poisoning is a condition developing as a result of external (exogenous) exposure of a human or animal body to chemical compounds in amounts that cause disorders of physiological functions and pose a hazard to life.

A syndrome is a set of symptoms sharing a common etiology and pathogenesis.

Somatogenic stage of poisoning is the period of acute chemical illness beginning after the elimination from the body or destruction of the toxic substance as a residual lesion of the structure and functions of various organs and systems, manifesting typically as various somatic, psychoneurological complications such as pneumonia, acute renal or hepatic failure, toxic polyneuropathy, anemia, psycho-organic syndrome, etc. In this stage of poisoning, specific (antidote) therapy is not required, and detoxification may be aimed solely at treating endotoxemia.

Toxicogenic stage of poisoning is the period of acute chemical illness beginning from the moment the toxic substance enters the body at a concentration capable of causing a specific effect and lasting until its elimination. It is characterized by the specificity of clinical manifestations reflecting the chemical and toxicological properties of the toxic substance and its impact on target organs. The severity of this period of the disease directly depends on the dose of the ingested poison and its concentration in the blood. The main therapeutic task in this period is the earliest possible reduction of its duration through the use of various methods of accelerated detoxification, antidote, and symptomatic therapy.

Antidepressants (thymoanalleptics) are medicinal products belonging to the group of psychoanaleptic agents that have a predominant effect on pathologically lowered mood or depressive affect. The mechanism of action of antidepressants consists in increasing the activity of serotonergic and/or noradrenergic neurotransmission.

MAO inhibitors (type A MAO inhibitors; non-selective MAO inhibitors) are medicinal products that reduce the activity of the enzyme monoamine oxidase found in brain tissues.

Antipsychotics (antipsychotic agents, APs) are a group of psychotropic medicinal products with psycholeptic action capable of reducing psychotic symptoms and psychomotor agitation (PMA). The antipsychotic effect of APs is mainly associated with the blockade of dopamine D₂ receptors and alteration of dopaminergic neurotransmission.

Normotimics (mood stabilizers) are medicinal products capable of smoothing out circular disorders of the affective sphere (mood swings), and in prophylactic use, preventing the development of depressive and manic symptoms. Normotimics include lithium preparations.

Psychostimulants (psychostimulants, agents used for attention deficit hyperactivity disorder, and nootropic drugs) are a group of psychotropic medicinal products that enhance mental and physical performance, improve the ability to perceive external stimuli (sharpen vision, hearing, etc., accelerate response times), elevate mood, relieve fatigue, and temporarily reduce the need for sleep.

Nootropics (other psychostimulants and nootropic drugs) are medicinal products that exert a specific positive effect on higher integrative brain functions, improve mental activity, cognitive functions, learning, and memory, and increase brain resistance to various damaging factors, including extreme loads and hypoxia. In addition, nootropics have the ability to reduce neurological deficit and improve cortico-subcortical connections.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Psychotropic drug poisoning is a condition that develops as a result of exposure of the body to high doses of psychotropic medicinal products, causing disorders of physiological functions and posing a hazard to health and life.

According to the national classification, psychotropic medicinal products include the following groups of medicinal preparations [1]:

A. Antipsychotics

B. Tranquilizers (anxiolytics)

C. Hypnotics and sedatives

D. Antidepressants

E. Mood-stabilizing preparations (lithium preparations)

F. Nootropic preparations (other psychostimulants and nootropic drugs)

G. CNS stimulants (psychostimulants, agents used for ADHD, and nootropic drugs)

Poisonings with tranquilizers (anxiolytics), hypnotics, and sedatives are represented in ICD-10 under category T42, "Poisoning by antiepileptic, sedative-hypnotic and antiparkinsonism drugs", and poisonings with other psychotropic substances under category T43, "Poisoning by psychotropic drugs, not elsewhere classified".

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

1.2.1. Etiology and pathogenesis of acute antidepressant poisoning

The main reasons for ingesting large doses of psychotropic substances in most cases are suicidal intentions, less commonly accidental poisoning or mistaken intake.

Classification of antidepressants by mechanism of action [2]:

I. Agents inhibiting neuronal monoamine uptake:

1. Non-selective action (non-selective monoamine reuptake inhibitors):

• blocking neuronal serotonin and norepinephrine uptake – tricyclic antidepressants (amitriptyline**, imipramine**, clomipramine**, mianserin, pipofezine**).

2. Selective action:

• selective serotonin reuptake inhibitors (SSRIs) – fluoxetine**, citalopram, paroxetine**, trazodone, mirtazapine, vortioxetine;

• selective serotonin and norepinephrine reuptake inhibitors (SNRIs, other antidepressants) – duloxetine, venlafaxine.

II. Monoamine oxidase inhibitors (MAOIs).

1. Non-selective action, inhibiting MAO-A and MAO-B (non-selective MAO inhibitors) – in Russia, non-selective MAO inhibitors have been withdrawn from circulation due to an unfavorable risk-benefit ratio)

2. Selective action, inhibiting MAO-A (type A MAO inhibitors) – pirlindole

Severe poisonings are most often caused by the use of tricyclic antidepressants (non-selective monoamine reuptake inhibitors) and non-selective MAO inhibitors. Selective neurotransmitter reuptake inhibitors and type A MAO inhibitors rarely cause severe poisoning when used alone.

The action of tricyclic antidepressants (TCAs) is based on the blockade of norepinephrine, serotonin, and partial dopamine reuptake. This leads to the accumulation of a large amount of mediators in the receptor area, significantly increasing their effects. Drugs of this group are to a greater or lesser extent reversible competitive blockers of M-cholinergic receptors, causing central and peripheral anticholinergic (cholinolytic) syndrome. Tricyclic antidepressants (non-selective monoamine reuptake inhibitors) also block peripheral α₁-adrenergic receptors, causing vasodilation and orthostatic hypotension. TCAs exert antihistamine effects, which enhance sedation and lower the "seizure threshold," which may contribute to the development of seizures.

Cardiotoxic effect of TCAs is due to a direct toxic impact on the cardiac conduction pathways. The drugs block sodium entry into cardiomyocytes of the myocardial conduction system. Impairment of depolarization in the cardiac conduction system slows the spread of excitation through the ventricular myocardium, which manifests as widening of the QRS complex on the ECG. Blockade of α-adrenergic receptors, along with decreased myocardial contractility, causes arterial hypotension. Simultaneous enhancement of sinus node activity (due to anticholinergic action) against the background of reduced conductivity in the AV junction, especially in Purkinje fibers, creates conditions for the development of ectopy and the formation of idioventricular rhythms with a wide QRS complex.

Selective serotonin reuptake inhibitors (SSRIs) came into use in the early 1980s and are still considered the drugs of choice for depression. Their efficacy is largely comparable to that of tricyclic antidepressants (TCAs), while their side effects are significantly less pronounced. Unlike TCAs, they do not bind to cholinergic or GABA receptors, and do not affect fast sodium channels or norepinephrine reuptake; therefore, anticholinergic (cholinolytic) effects are much less characteristic of them. Sedation and orthostatic hypotension rarely occur during their use, and the risk of cardiotoxic effects is significantly lower. However, SSRIs present a high danger when taken in combination with narcotic analgesics, MAOIs, and MAOI-As due to the high probability of developing serotonin syndrome.

Monoamine oxidase inhibitors (MAOIs and MAOI-As) began to be used in the early 1950s. Structurally, some MAO inhibitors have amphetamine-like activity. MAO inhibitors block the activity of the enzyme that breaks down norepinephrine, dopamine, and serotonin, resulting in the formation of an excess of catecholamines and hypertensive syndrome. Since MAO is localized in many organs, poisoning with drugs that inhibit it is often accompanied by the development of ischemic organ damage (liver, heart, etc.). When MAOIs and MAOI-As are combined with other pharmacological agents (antihypertensive drugs, antiarrhythmics, narcotic analgesics, SSRIs), poisonings may be accompanied by the development of serotonin syndrome, a rare but life-threatening bodily reaction to high doses of drugs that enhance serotonergic transmission. The risk of this disorder is particularly high when combining MAOI (MAOI-A) antidepressants and SSRIs. MAO inhibitors are capable of inhibiting pyridoxine-dependent enzymes (pyridoxine phosphokinase, dopa decarboxylase, glutamate decarboxylase) and thereby provoking the development of convulsive syndrome, which usually develops at the height of delirium.

Pharmacokinetics.

Absorption. Antidepressants are lipophilic compounds, rapidly and almost completely absorbed in the gastrointestinal tract. The bioavailability of amitriptyline** is 30–60%, imipramine** is 22–77%, and pipofezine** is about 80% [3]. On average, the time to reach maximum serum concentration is 2–8 hours. $T$_½ varies from 7 to 58 hours. Antidepressants are substances with large volumes of distribution (15–40 L/kg). Tricyclic antidepressants are weak bases with high pKa, so changes in acid-base balance affect the degree of molecule ionization.

Distribution and metabolism. The blood-to-tissue distribution ratio ranges from 1:10 to 1:30, respectively, with predominant accumulation of the drugs in brain, liver, and myocardial tissue. This fact explains the low efficacy of forced diuresis and hemodialysis in antidepressant poisoning. Plasma protein binding is high; for instance, it is 95% for amitriptyline**, 85% for imipramine**, and 90% for pipofezine**. The volume of distribution for amitriptyline** is 20 L/kg, for clomipramine** from 7 to 20 L/kg, and for imipramine** 15 L/kg [4]. The drugs undergo significant biotransformation in the liver with the formation of inactive metabolites.

They are excreted from the body mainly by the kidneys. The plasma half-lives ($T$_½) are 17–40 hours for amitriptyline**, 33–37 hours for citalopram, 24–144 hours for fluoxetine**, and 3–44 hours for paroxetine**. A characteristic feature of drugs in this group is the enterohepatic circulation, which contributes to the prolonged course of the toxicogenic stage [5].

Toxic effects manifest when doses exceed 500 mg, and death occurs with a single intake of amitriptyline in doses exceeding 1200 mg. The plasma concentration of TCAs corresponding to severe poisoning is more than 1 µg/mL. The narrow therapeutic concentration range of antidepressants determines a high risk of poisoning even when these medications are taken in therapeutic doses. Therapeutic, toxic, and lethal blood concentrations of certain antidepressants are given in the table.

Table 1 – Therapeutic, toxic, and lethal concentrations of antidepressants (according to Bulletin of TIAFT, 1996) [6]

1.2.2. Etiology and pathogenesis of acute antipsychotic (neuroleptic) poisoning

Antipsychotics (neuroleptics) are generally subdivided into "typical" and "atypical" neuroleptics (NL). The main difference is that "typical" drugs are characterized by such a side effect as extrapyramidal system dysfunction (parkinsonism and other movement disorders occur) [2]:

I. Typical neuroleptics:

1. phenothiazine derivatives (aliphatic phenothiazine derivatives, piperazine phenothiazine derivatives, piperidine phenothiazine derivatives) (chlorpromazine**, trifluoperazine**, levomepromazine**, perphenazine**, periciazine**);

2. thioxanthene derivatives (chlorprothixene, flupentixol**);

3. butyrophenone derivatives (haloperidol**, droperidol**);

II. Atypical neuroleptics:

1. benzamides (sulpiride**, tiapride);

2. dibenzodiazepine derivatives (diazepines, oxazepines, thiazepines, and oxepines) (clozapine, quetiapine**).

Neuroleptics (antipsychotic drugs) are serotonin and dopamine receptor antagonists. Drugs of this group exert an antipsychotic and, to varying degrees, sedative (calming) effect. The antipsychotic effect manifests as the elimination of positive symptoms of psychoses (delusions, hallucinations). The psychosedative action is characterized by general calming, reduction of anxiety and distress, decreased motor activity, and diminished aggressiveness.

The primary neurochemical action of antipsychotic drugs is based on the blockade of receptor systems—predominantly dopamine and serotonin—responsible for the development of psychosis. For most drugs in this group, this effect is associated with the blockade of postsynaptic dopamine D₂ receptors in the limbic system. Suppression of transmission in the mesolimbic system is responsible for the antipsychotic effect, in the nigrostriatal pathway for extrapyramidal side effects, and in the tuberoinfundibular zone for neuroendocrine disorders, including hyperprolactinemia. The sedative effect of antipsychotics is linked to their influence on the ascending reticular formation of the brainstem. For certain antipsychotics (e.g., aliphatic, piperazine, and piperidine phenothiazine derivatives), their blocking effect on brain serotonin receptors and M-cholinergic receptors may be important in the development of psychotropic effects.

Typical antipsychotics primarily affect dopamine receptors, whereas atypical neuroleptics predominantly influence the metabolism of serotonin and other neurotransmitters; accordingly, they less frequently cause extrapyramidal disorders. Typical neuroleptics lower the seizure threshold, which can lead to epileptic seizures. With the use of "atypical" antipsychotics, this effect is observed relatively rarely or is weakly expressed.

It is believed that the more pronounced the dopaminolytic effect of a drug, the higher its antipsychotic potential and the greater the development of extrapyramidal disorders. In rare cases, neuroleptic malignant syndrome develops. Its development is based on the blockade of striatal D₂ receptors, which causes muscular rigidity and tremor, leading to intense heat production. The decrease in dopamine also disrupts the regulation of serotonergic structures in the striatum and hypothalamus, which are responsible for thermoregulation processes. In addition to affecting dopamine and serotonin receptors, many neuroleptics block receptors of other neurotransmitter systems in the brain and autonomic nervous system. For example, blockade of M-cholinergic receptors, α₁-adrenergic receptors, and H₁-histamine receptors leads to a sedative effect, central and peripheral anticholinergic syndrome, and hypotension. A number of neuroleptics (thioridazine**) exhibit cardiotoxic effects.

Mechanism of neuroleptic toxic action:

1. Blockade of CNS dopaminergic systems with the development of extrapyramidal disorders and malignant hyperthermia.

2. Blockade of α₁-adrenergic receptors, leading to arterial hypotension.

3. Blockade of M-cholinergic receptors, manifested by central and peripheral anticholinergic syndrome.

4. Cardiotoxic action—blockade of fast sodium channels, manifested by widening of the QRS complex and suppression of myocardial contractility, as well as blockade of potassium channels, leading to QT interval prolongation and torsades de pointes.

Table 2 – Mechanism of toxic action of certain neuroleptics [5]

Toxicokinetics of antipsychotics. Antipsychotics, particularly aliphatic, piperazine, and piperidine phenothiazine derivatives, are highly soluble in water and lipids and are rapidly absorbed from the gastrointestinal tract. Peak blood concentrations are reached 2–4 hours after administration. Biotransformation of antipsychotics occurs in the liver. The main pathways of biotransformation are: hydroxylation of aromatic rings; oxidation of the sulfur atom in the heterocycle to sulfoxide or sulfone; N-dealkylation at the nitrogen atom or side chain. Drugs in this group circulate as part of the enterohepatic cycle. Metabolites (and in minor amounts, parent compounds) are excreted by the liver and kidneys. The duration of effect depends on enterohepatic circulation and metabolite activity. When very high doses are taken, elimination is prolonged up to 6 days. Hydroxylated derivatives of the drugs are excreted in the urine.

Table 3 – Pharmacological properties of certain antipsychotics [5]

Toxicity, lethal doses, and concentrations. Antipsychotics have a rather narrow therapeutic index (Table 4).

Table 4 – Therapeutic, toxic, and lethal concentrations of certain antipsychotics [6]

1.2.3. Etiology and pathogenesis of lithium poisoning

Lithium is an alkali metal, and therefore it is used in medicine in the form of salts, mainly as lithium carbonate, as well as lithium citrate, succinate, orotate, chloride, and sulfate. In Russia, only lithium carbonate is used among lithium salts.

Lithium has a complex mechanism of action that is not yet fully understood. Being a monovalent cation, lithium enters the cell through fast sodium channels, where it partially replaces sodium. However, lithium ions exit cells more slowly, which disrupts the rate of exchange of extra- and intracellular sodium and potassium ions. As a result of electrolyte dissociation, the process of depolarization and nerve impulse propagation is impaired. Nevertheless, the long latency period between lithium administration and the onset of its effect indicates that the effect of lithium is not solely due to rapid biochemical processes. In recent years, the effect of lithium on intracellular signals and neuronal growth and development has been studied. Currently, it is believed that the mechanism of action of lithium is related to the depletion of inositol stores in the central nervous system [5]. There is evidence of lithium's effect on the release of serotonin, norepinephrine, and dopamine.

Lithium salts are rapidly absorbed in the gastrointestinal tract. Peak serum concentration is reached in 1–2 hours. When high doses of the drug are taken, the peak serum concentration is reached later, and multiple peaks are possible. The volume of distribution of lithium is 0.6–0.9 L/kg. The drug does not bind to plasma proteins and is freely distributed in all body fluids. The drug crosses the blood-brain barrier slowly. Lithium is excreted by the kidneys—95%, with the remaining 5% excreted in feces. The process of lithium reabsorption in the renal tubules directly depends on sodium concentration: in case of insufficient sodium, lithium undergoes reabsorption and its concentration in the blood increases. Thus, sodium chloride** serves as a natural antidote in lithium poisoning.

1.2.4. Etiology and pathogenesis of acute poisoning with psychostimulants, ADHD medications, and nootropics

Psychostimulants, ADHD medications, and nootropics are a group of psychotropic drugs that have an excitatory effect on the mental and physical state of the organism. Undesirable properties of this group of medications include rapidly developing drug dependence (physical and psychological). The drugs are prescribed for asthenic conditions of various origins, attention deficit hyperactivity disorder (ADHD), stuporous states, neurotic disorders with inhibition, and narcolepsy. Centrally acting anti-obesity drugs have a similar mechanism of action and can cause a similar clinical picture in overdose.

Among the drugs of this group, caffeine** and the fixed combination of mesocarb + adamantylbromophenylamine are registered in the Russian Federation. Mesocarb, as part of the drug, exerts its psychoactivating effect through the stimulation of catecholaminergic systems, including noradrenergic and dopaminergic systems, which can lead to the depletion of neuronal stores, while adamantylbromophenylamine enhances de novo dopamine synthesis by stimulating tyrosine hydroxylase gene expression and exhibits antioxidant and immunomodulatory effects.

Pharmacokinetics. After oral administration, both components of the drug are well distributed in organs and tissues, cross the blood-brain barrier, and undergo biotransformation in the liver. The T1/2 for mesocarb is 18.2 h, and for adamantylbromophenylamine, it is 55.4 h.

Xanthine derivatives. A drug from the methylxanthine group (xanthine derivatives) is caffeine**. It is an alkaloid found in tea leaves, coffee beans, cocoa, and other plants. A distinctive feature of caffeine** is the combination of psychostimulant and analeptic action. Analeptic activity is associated with the direct stimulating effect of caffeine** on the respiratory and vasomotor centers of the medulla oblongata. Caffeine** has a tonic effect on cerebral vessels, which explains its effectiveness in migraines. The drug is available in tablet and injectable forms, and it is also part of many combination products containing non-narcotic analgesics and other substances. With prolonged use of caffeine**, mild tolerance develops. Psychological dependence (theism) may occur. The psychostimulant effect of caffeine** is due to its ability to block central adenosine (A₁ and A₂) receptors. Adenosine (an intermediate product of ATP metabolism), by exciting brain A₁ receptors, reduces the formation of cyclic adenosine monophosphate (cAMP), which leads to the suppression of the functional activity of neurons (inhibition). Through A₂ receptors, adenosine suppresses the activity of brain D₂ dopamine receptors. By eliminating the inhibitory action of adenosine, caffeine** causes central nervous system excitation and activates the dopaminergic system. A feature of caffeine** action is that it enhances the activity of neurons that are currently involved in physiological responses and in which cyclic nucleotides are synthesized in response to neurotransmitters.

Due to excessive central and peripheral adrenergic stimulation, psychostimulant medications exhibit neurotoxic (psychopathic) and cardiotoxic effects. In addition, prolonged or excessive strain on the adrenergic system can lead to the depletion of catecholamine stores and the breakdown of the sympathoadrenal system of urgent adaptation.

Caffeine** is a lipophilic compound, rapidly and completely absorbed in the gastrointestinal tract. The bioavailability of caffeine** is 100%. The time to reach peak concentration is 30–45 minutes. The half-life is 2–4 hours. The main metabolic pathways involve the demethylation of various nitrogen atoms. Demethylation of the N₃ atom leads to the formation of paraxanthine; demethylation of the N₁ atom produces theophylline (a vasodilator that enhances cerebral and muscular blood flow); a N₇-demethylated derivative of caffeine** is theobromine (a relaxant of muscle fibers, bronchioles, and blood vessels). Metabolism is carried out by the hepatic cytochrome P450 system in the following ratio: 84% of caffeine** is metabolized to paraxanthine, 12% to theobromine, and 4% to theophylline. About 10% of caffeine** is excreted unchanged by the kidneys. The toxic effect of caffeine** manifests at blood concentrations above 10 mg/mL. A dose exceeding 10 g is considered lethal.

Nootropic drugs (other psychostimulants and nootropics) activate higher integrative functions of the brain—they stimulate mental activity, improve memory, facilitate learning processes, and increase the brain's resistance to various harmful influences. This group of drugs includes pyrrolidone and pyridoxine derivatives (other psychostimulants and nootropics) such as piracetam**, fonturacetam**; GABA derivatives and analogues (other psychostimulants and nootropics) such as gamma-aminobutyric acid, nicotinoyl gamma-aminobutyric acid, aminophenylbutyric acid; neuropeptides and their analogues (other psychostimulants and nootropics) such as omberacetam, methionyl-glutamyl-histidyl-phenylalanyl-prolyl-glycyl-proline**, pyridoxine + threonine, glycine**; vitamin-like agents (other psychostimulants and nootropics) such as idebenone. Their pharmacological action is based on affecting the metabolic (energy) processes of the brain—enhancing the synthesis of high-energy phosphates and proteins, and activating a number of enzymes. Some drugs mimic the metabolic effects of GABA.

Other psychostimulants (general tonic drugs). This group includes herbal medicinal products used as tonics—alcohol tinctures and extracts: ginseng root, prickly eleutherococcus rhizomes and roots, schisandra chinensis seeds, rhodiola rosea rhizomes and roots, manchurian aralia root, leuzea carthamoides rhizomes and roots. The mechanism of action of these drugs has been insufficiently studied, but long-term experience has shown that they exert a stimulating (tonic) effect on the central nervous system and overall body functions.

1.3 Epidemiology of the Disease or Condition

According to toxicological centers in our country, poisonings with psychotropic drugs rank third in the structure of acute poisonings, after poisonings with drugs of abuse and alcohol-containing products. The mortality rate in this group of poisonings is 1.7%. The most frequent cause of fatal outcomes is poisoning with TCAs [6, 8, 9]. Over the past 5 years, a 1.7-fold increase in acute antidepressant poisonings has been noted, primarily among young, able-bodied individuals. A decrease in the number of TCA poisonings is registered, while the number of SSRI poisonings has increased: fluvoxamine by 1.3 times, fluoxetine** by 1.6 times, and sertraline** by 8 times. The cause of poisoning is suicidal intent in 72–77% of cases, recreational purposes in 10–15%, and self-medication in 10–18%. The proportion of patients aged 16–30 years increased from 25% to 48.6%, while the proportion of individuals aged 60 and older decreased from 25% to 16% [10]. The main neuroleptic drugs causing severe poisonings are butyrophenone derivatives as well as aliphatic, piperazine, and piperidine phenothiazine derivatives. A severe clinical course with a high probability of complications is also characteristic of poisoning with dibenzodiazepine-range neuroleptics (diazepines, oxazepines, thiazepines, and oxepines)—clozapine [6].

One of the causes of neuroleptic poisoning can be iatrogenic overdoses. When using antipsychotic drugs, side effects may develop in the form of neuroleptic malignant syndrome or treatment-resistant acute extrapyramidal syndrome, which can also serve as a reason for hospitalization in toxicological departments.

1.4 Features of Coding the Disease or Condition

Poisoning by psychotropic drugs, not elsewhere classified (T43) according to ICD-10, is included in the group: T36–T50 – Poisoning by drugs, medicaments and biological substances (T36–T50).

Category T43 Poisoning by psychotropic drugs, not elsewhere classified.

Subcategories.

• T43.0 Poisoning by tricyclic and tetracyclic antidepressants.

• T43.1 Poisoning by monoamine oxidase inhibitor antidepressants.

• T43.2 Poisoning by other and unspecified antidepressants.

• T43.3 Poisoning by antipsychotic and neuroleptic drugs.

• T43.4 Poisoning by neuroleptics of the phenothiazine, butyrophenone, and thioxanthene series.

• T43.5 Poisoning by other and unspecified antipsychotic and neuroleptic drugs.

• T43.6 Poisoning by psychostimulants with potential for abuse.

• T43.8 Poisoning by other psychotropic drugs, not elsewhere classified.

• T43.9 Poisoning by unspecified psychotropic drugs.

Comments: according to the Table of drugs and chemicals causing poisoning or other adverse reactions (ICD-10, Volume 3), the following belong to subcategories:

• T43.5 "Poisoning by other and unspecified antipsychotic and neuroleptic drugs" includes poisonings by lithium preparations;

- Lithium carbonate;

• T43.6 "Poisoning by psychostimulants with potential for abuse" includes poisonings by drugs of the group "psychostimulants, agents used for ADHD, and nootropics";

- Caffeine**;

• T43.8 "Poisoning by other psychotropic drugs, not elsewhere classified" includes fatty acid derivatives;

- Gamma-aminobutyric acid.

1.5 Classification of the disease or condition

Depending on the clinical presentation of the disease, acute poisonings by psychotropic drugs vary in severity. When determining severity, only actual clinical symptoms must be taken into account, without assessing risk based on parameters such as the amount of ingested poison and serum drug concentrations. Criteria for assessing poisoning severity have been proposed by members of the European Association of Poisons Centres and Clinical Toxicologists (Appendix G1).

1.6 Clinical presentation of the disease or condition

1.6.1. Clinical presentation of antidepressant poisoning

Poisoning symptoms generally appear 2–3 hours after drug administration. Frequently, only minimal symptoms are detected upon admission, but severe cardiovascular and central nervous system disorders may develop over the next few hours. TCAs have a low toxic threshold; therefore, a dose of 10–20 mg/kg can exert a pronounced toxic effect on the aforementioned systems. Acute antidepressant poisonings are characterized by the following disorders:

• acute toxic damage to the central nervous system;

• M-anticholinergic effect (central and peripheral type anticholinergic syndrome);

• cardiovascular disorders;

• serotonin syndrome.

Acute toxic damage to the central nervous system manifests mainly as varying degrees of impaired consciousness—from lethargy to deep coma. Epileptic seizures, developing within the first two hours of poisoning, are observed less frequently. They are usually short-lived and generalized. The combination of convulsive and anticholinergic syndromes is considered extremely dangerous and prognostically unfavorable, even in the absence of cardiac rhythm disturbances.

Anticholinergic syndrome ("anticholinergic toxidrome") of the central type clinically manifests as agitation against a background of confusion (the so-called "anticholinergic intoxication") or depressed consciousness. Various types of consciousness disorders are noted (disorientation in space, place, time, hallucinations, delusions, agitation or delirium, and depression of consciousness ranging from stupor to coma). Moreover, at toxic doses, the most pronounced productive symptoms develop in TCA poisoning. Peripheral anticholinergic syndrome manifests as skin flushing and dryness, dry mouth, mydriasis, accommodation disorders (blurred and indistinct near vision, inability to focus eyes at close range), tachycardia, weakened intestinal peristalsis up to the development of paresis, and urinary retention (the urinary bladder is generally palpable). Myoclonus or choreiform movements are noted. The clinical picture of the anticholinergic syndrome can be recognized by the mnemonic: "blind as a bat, red as a beet, hot as a hare, dry as a bone, mad as a hatter" [8].

Cardiovascular disorders in antidepressant poisoning are caused by the direct toxic effect of the toxicant on myocardial contractility and the cardiac conduction system, as well as by a decrease in total peripheral vascular resistance. This effect of antidepressants is referred to as the primary cardiotoxic effect (PCE). In antidepressant poisoning (predominantly TCAs), the primary cardiotoxic effect occurs in 21.5% of patients when the blood drug concentration exceeds 4.5 µg/mL. Characteristic ECG signs of PCE include the development of complete bundle branch block, in half of the cases combined with first-degree AV block. Widening of the QRS complex beyond 120 ms and its deformation is a precursor of life-threatening cardiac arrhythmias and a marker of neurological complications. In 33% of patients with a QRS complex width greater than 100 ms, epileptic seizures develop. When the QRS complex widens to 160 ms, the risk of ventricular arrhythmias increases to up to 50%. If no QRS complex widening greater than 100 ms is recorded within 6 hours after poisoning, the risk of arrhythmias and seizures is considered minimal. TCAs cause typical ECG changes that allow for diagnosis even in cases where the anamnesis and physical examination are uninformative. The QRS complex width in limb leads has the highest diagnostic sensitivity. At the same time, a deep S wave in lead I and a tall R wave in lead aVR are recorded. Paroxysmal forms of rhythm disorders, such as supraventricular and ventricular paroxysmal tachycardia, are characteristic in the presence of anticholinergic syndrome and are associated with the parasympatholytic action of the toxicant. Blockade of postsynaptic α₁-adrenoceptors in TCA poisoning leads to decreased peripheral vascular resistance and arterial hypotension. Clinically, the cardiotoxic effect manifests as skin pallor (mottling), weak pulse volume with a heart rate of 60–70 bpm, low blood pressure, and decreased stroke volume and cardiac output. Hypovolemia in this context is relative. The decrease in circulating blood volume does not exceed 12–25%. These clinical signs indicate the development of cardiogenic exotoxic shock. At the same time, a 40–60% decrease in cardiac contractility is observed.

In MAOI and MAOI-A poisoning, an "adrenergic syndrome" develops, clinically manifested by high blood pressure, pale and clammy skin. As the drug concentration in plasma increases, the "adrenergic syndrome" transforms into an "anticholinergic syndrome". A decrease in blood pressure is observed due to reduced cardiac output. With prolonged exposure to the toxicant, an "α-adrenolytic syndrome" develops, which is characterized by a sharp drop in blood pressure. The phasic nature of these three types of systemic hemodynamic changes ("adrenergic" syndrome → "anticholinergic" syndrome → "α-adrenolytic" syndrome) occurs with the development of the concurrent quinidine-like action of antidepressants, which is why the risk of arrhythmia persists throughout the entire toxicogenic phase of poisoning.

Serotonin syndrome is the most common and severe adverse effect of selective serotonin reuptake inhibitors (SSRIs), especially when taken concomitantly with MAOIs and MAOI-As. Manifestations of serotonin syndrome include altered mental status, psychomotor agitation, myoclonus, hyperreflexia, diaphoresis, tremor, diarrhea, coordination disorders, muscle rigidity, and hyperthermia. Prolonged severe hyperthermia can cause lactic acidosis and rhabdomyolysis with renal and hepatic impairment.

The severity of antidepressant poisoning depends on the degree of cardiac dysfunction (presence and severity of PCE) and mental status impairment.

Mild poisoning is characterized by initial symptoms of impaired consciousness: somnolence, stupor, disorientation; visual hallucinations may occur. In 30% of patients, a peripheral-type anticholinergic syndrome develops (skin hyperemia, dry mucous membranes, mydriasis, tachycardia, moderate arterial hypertension).

Moderate severity poisoning is characterized by superficial or deep stupor. In 8–10% of cases in a stuporose state, a central-type (motor agitation, auditory and visual hallucinations) and peripheral-type (tachycardia, arterial hypertension, mydriasis, hyperemia, dry skin) anticholinergic syndrome occurs. The development of arrhythmias and aspiration-obstructive respiratory disorders is possible.

Severe poisoning is characterized by profound depression of consciousness (coma). In 24.6% of poisoning cases, the comatose state is accompanied by mixed-type respiratory impairment. Anticholinergic syndrome is observed only after the patient emerges from the comatose state, presenting initially as central and then progressing to peripheral. Seizure activity is noted in 6% of patients. A characteristic feature is the widening of the QRS complex to 0.11-0.12 s or more, up to complete atrioventricular block accompanied by bradycardia, which is an unfavorable prognostic sign.

Complications. Complications develop in both the toxicogenic and somatogenic stages of poisoning. The toxicogenic stage is characterized by exotoxic shock, respiratory disorders, and seizures, which corresponds to the clinical manifestations of severe antidepressant poisoning. In the somatogenic stage, tracheobronchitis, pneumonia, cerebral edema, and myorenal syndrome with acute kidney injury develop most frequently. The frequency of these complications depends on how quickly the victim was hospitalized, examined, and adequate treatment was initiated.

The immediate causes of death are: in the toxicogenic stage — acute poisoning with life-threatening intraventricular conduction disorders, ventricular fibrillation, decompensated exotoxic shock, status epilepticus with hyperthermia, and respiratory disorders. Therefore, if antidepressant poisoning is suspected or diagnosed, the patient must undergo an ECG examination (electrocardiogram recording). In cases of moderate and severe poisoning, continuous 24-hour monitoring of cardiac activity (electrocardiographic data monitoring) and blood pressure (ambulatory blood pressure monitoring) must be ensured, and the patient placed in an intensive care unit/ward until consciousness and spontaneous adequate breathing are restored, and the ECG normalizes (the QRS complex must be less than 0.1 s).

In the somatogenic stage, the cause of death can be cardiovascular failure and respiratory failure against the background of severe purulent-septic complications, sepsis, multiple organ dysfunction syndrome, and myorenal syndrome.

Selective serotonin and norepinephrine reuptake inhibitors (classified under the ATC group "other antidepressants") rarely cause severe poisoning. Unlike TCAs and MAOis (MAOI-As), they do not exert anticholinergic and $\alpha$-adrenoreceptor blocking effects, do not cause sedation, and the risk of cardiotoxic effects in poisoning with drugs from these groups is significantly lower. In poisoning with selective serotonin reuptake inhibitors, early signs of toxicity include: nausea, vomiting, blurred vision, and less frequently — CNS depression and sinus tachycardia. Seizures and QRS complex widening have been described, but they are rare. An exception is citalopram, overdose of which results in QT prolongation and seizures (both effects are dose-dependent). Fast sodium channel blockade is usually clinically silent, although fatal cases of QRS widening and sinus tachycardia have been reported.

1.6.2. Clinical presentation of neuroleptic (antipsychotic) poisoning

The clinical course resembles that of hypnotic drug poisoning, presenting with a dose-dependent toxic effect — altered states of consciousness ranging from somnolence to coma. Many neuroleptics, possessing strong antimuscarinic activity, can cause anticholinergic syndrome, which clinically manifests as tachycardia, reduced salivation and sweating, skin flushing and dryness, mydriasis (or, conversely, miosis in some cases), decreased bowel motility, and urinary retention. Central anticholinergic syndrome (delirium) may occur. A moderate increase in body temperature is frequently noted due to impaired heat dissipation resulting from decreased sweating and increased heat production. Arterial hypotension develops ($\alpha_1$-adrenolytic syndrome). ECG changes are identical to those seen in TCA poisoning (widening of the QRS complex, QT interval prolongation, torsades de pointes).

The development of intoxication is characterized by a sequence of phases due to the effect of neuroleptics on various neurotransmitter structures. Thus, in moderate poisoning with aliphatic, piperazine, piperidine phenothiazine derivatives, and thioxanthene derivatives, an anticholinergic syndrome develops, which, as the intoxication progresses, is replaced by an alpha-adrenergic blocking syndrome that transitions into exotoxic shock. It should be noted that aliphatic, piperazine, and piperidine phenothiazine derivatives cause a profound blockade of alpha-adrenoceptors in the terminal vascular bed, which accounts for the resistance of hypotension to ongoing therapy.

Poisoning with neuroleptics exhibiting pronounced dopaminolytic activity leads to extrapyramidal disorders. High-potency neuroleptics (haloperidol**) cause extrapyramidal disorders significantly more often compared to low-potency ones (chlorpromazine**, thioridazine**). Neuroleptic syndrome (neuroleptic extrapyramidal disorders) is a complex of neurological complications manifested by motor disorders. According to the American classification DSM-IV, all extrapyramidal movement disorders can be divided into parkinsonism (akinetic-rigid and hyperkinetic-rigid syndrome), acute dystonia (dyskinetic syndrome), and acute akathisia (hyperkinetic syndrome) [11].

Neuroleptic parkinsonism includes bradykinesia (slowed pace of movements, difficulty initiating movements, difficulty turning), rigidity (stiffness, muscle tension), cogwheel phenomenon (interrupted, stuttering movements), limb tremor, masked facies, and salivation.

Acute dystonia (early dyskinesia) manifests as involuntary movements in the form of spastic contractions of individual muscle groups throughout the body. This involves rotation, flexion, or extension of the trunk and limbs with the formation of abnormal postures (torsion spasms); paroxysmal tension of the facial and pharyngeal muscles, forced tongue protrusion, difficulty swallowing, breathing, and speech, forced head turning to the side or backward (Kulenkampff-Tarnow syndrome); choreoathetosis – a combination of chorea (rapid, jerky movements) and athetosis (slow convulsive movements). These two types of abnormal movements (chorea and athetosis) coexist, although one component may be more pronounced. Athetosis in the fingers manifests as slow, writhing, worm-like movements. Athetosis of the facial muscles manifests as grimacing, twitching of the lips and tongue. Chorea consists of diverse, rapid, involuntary, non-rhythmic, and non-sequential movements of the muscles of the trunk, limbs, neck, and face.

Akathisia is a condition characterized by an irresistible urge to move and change posture («restless legs» syndrome; patients «fidget» in bed, unable to find a comfortable position, with observed fussiness and agitation).

Neuroleptic malignant syndrome. The agents most frequently causing its development are haloperidol**, aliphatic, piperazine, and piperidine phenothiazine derivatives, butyrophenone derivatives, and thioxanthene derivatives. The development of the syndrome is manifested by progressive muscle rigidity and a fever resistant to antipyretic therapy. The clinical symptoms progress over 24–72 hours. The syndrome occurs against the background of hyperhidrosis, leading to additional fluid loss. The main clinical manifestations are muscle rigidity, hyperthermia (most often febrile), autonomic shifts, and mental disorders [12]. The severity of muscle rigidity varies from muscle hypertonus to the «lead-pipe» sign, where extreme resistance to passive movements is observed. In neuroleptic malignant syndrome, the following extrapyramidal disorders may be observed: bradykinesia and akinesia, cogwheel sign, myoclonus, tremor, chorea, opisthotonos, dysarthria, aphonia, dysphagia, akathisia, dystonia, epileptiform seizures, hyperreflexia, nystagmus, and incoordination. Somatic disorders in neuroleptic malignant syndrome, caused by autonomic nervous system dysfunction, are diverse: tachycardia and other cardiac dysrhythmias, blood pressure lability, tachypnea, skin pallor, diaphoresis, salivation, and urinary incontinence. Symptoms of dehydration are observed: dryness of mucous membranes, sunken eyes, and decreased skin turgor. Mental disorders in neuroleptic malignant syndrome are diverse: ranging from anxiety, confusion, agitation, or delirium to severe catatonia, akinetic mutism, stupor, and coma. The consequences of neuroleptic malignant syndrome include:

• hypotension, dehydration, shock;

• rhabdomyolysis, acute kidney injury;

• development of arrhythmias due to metabolic acidosis and the direct cardiotoxic effect of neuroleptics.

In mild neuroleptic poisoning, the main symptoms are lethargy, apathy, general weakness, and dizziness. Subsequently, drowsiness and muscle hypotonia appear, developing into prolonged sleep from which patients can be aroused only with difficulty and for a short time. In chlorprothixene poisoning, mydriasis is recorded; in poisonings with aliphatic, piperazine, piperidine phenothiazine derivatives and haloperidol**, miosis is observed. Respiratory and cardiovascular system functions are usually not impaired. Moderately severe tachycardia may appear. Mild extrapyramidal disorders may develop—hypokinesia, nuchal rigidity, trismus, and tremor—which can resolve spontaneously.

In moderate poisoning, depression of consciousness to the level of stupor with periodic periods of agitation is observed. Pupillary constriction is more characteristic, but dilation may also occur. Reflexes may be diminished, but hyperreflexia is more frequently observed; muscle dystonia may occur. Nuchal rigidity, trismus with forced grimaces, limb spasticity, torticollis, oculogyric crisis, athetosis-like seizures, and occasionally pathological reflexes and cataleptoid states are noted. Dyspnea may occur, and with prolonged respiratory impairment and hypotension, cyanosis may appear. A decrease in body temperature is usually recorded, although in some cases moderate poisoning proceeds with hyperthermia. Intestinal paresis and urinary retention occur relatively frequently.

Severe poisoning is characterized by the development of coma. Breathing becomes shallow and stertorous, later acquiring a periodic character (Cheyne-Stokes type). The skin is pale, covered with cold, clammy sweat, and cyanosis appears. Reflexes may be enhanced but are subsequently lost, and the pupillary light reflex disappears. Signs of heart failure appear, manifested by hypotension, tachycardia, and a pulse of low volume and tension. Convulsions sometimes occur: clonic, tonic, opisthotonos-like, and carpopedal spasm-like. Severe forms of extrapyramidal syndrome include the development of serial torsion spasms (tonic contraction of trunk muscles with twisting), serial paroxysms of Kulenkampff-Tarnow syndrome, and other motor crises with dyskinesias and autonomic disorders manifesting as serial seizures. Convulsions are usually mild but prolonged and repetitive. In terms of onset, convulsions may precede respiratory center depression or occur against the background of developing coma or collapse. Death results from respiratory center paralysis or the development of cardiovascular failure.

Complications. A typical late complication leading to a fatal outcome is pneumonia. Against the background of central nervous system function recovery, even after the symptoms of acute poisoning have disappeared, parkinsonoid phenomena with tremor and spasticity may occur. Long-term persistence of headaches, depression, and the development of retrograde amnesia are possible.

Features of the clinical picture of poisonings with certain neuroleptics.

Chlorpromazine** is a phenothiazine derivative with a broad spectrum of action. The drug has a pronounced effect on both the central and peripheral nervous systems. Chlorpromazine** is characterized by a sedative effect and the ability to induce extrapyramidal disorders. A distinctive feature of chlorpromazine** is its myorelaxant effect. This is associated with the depression of supraspinal regulation of muscle tone, primarily through action on the basal ganglia. Chlorpromazine** inhibits the vomiting reflex by blocking dopamine receptors in the trigger zone located at the floor of the fourth ventricle. Chlorpromazine** also affects peripheral innervation. The most pronounced is the α-adrenolytic effect, which results in the "perversion" of the epinephrine effect and a decrease in blood pressure. As a result of the M-cholinolytic action of chlorpromazine**, poisoning with this drug is accompanied by a decrease in the secretion of salivary, bronchial, and digestive glands. In rare cases, neuroleptic malignant syndrome develops. It is believed to be the result of idiosyncrasy to the prescribed drug, and 10–20% of such patients die.

Trifluoperazine** is a phenothiazine derivative characterized by less pronounced sedative, hypotensive, and myorelaxant effects. However, the risk of extrapyramidal disorders is higher than that of chlorpromazine.

Chlorprothixene. The drug causes a pronounced sedative effect, possesses antiemetic properties, and has a mildly expressed hypotensive action.

Haloperidol** is a butyrophenone derivative. The high antipsychotic activity of haloperidol** in poisonings manifests as a severe extrapyramidal syndrome. The sedative effect is mildly expressed. The drug is characterized by insignificant depression of peripheral α-adrenoceptors and the absence of ganglion-blocking atropine-like action, meaning the drug does not lower blood pressure or cause a anticholinergic syndrome.

Sulpiride** is a benzamide derivative. The drug is a selective D2 dopamine receptor blocker, so extrapyramidal disorders in poisoning are mild. In sulpiride** poisoning, minor hypotension and a slight sedative effect are possible.

Clozapine is an antipsychotic with a pronounced sedative effect. A distinctive feature of these poisonings is their severe clinical course and high mortality rate, reaching up to 30% [13]. The clinical picture of clozapine poisoning is specific. It is believed that the pharmacological action of clozapine involves several components (central and peripheral anticholinergic, α-adrenolytic, antiserotonin, and antihistamine effects, as well as the inhibition of presynaptic dopamine release). The opinions of various authors regarding the leading mechanism differ significantly. Nevertheless, the majority of authors consider the central anticholinergic effects to be the most prominent in poisoning.

The kinetics of the drug have been well studied. The most significant parameters include rapid absorption after oral administration (maximum blood concentration reached in 2 hours), high absorption (90–95%) and bioavailability of 50–60%, and significant plasma protein binding (95%). Clozapine metabolism occurs mainly in the liver via cytochrome P4501A2 and P4503A4 through demethylation, aromatic ring oxidation, and conjugation, resulting in the formation of active (desmethylclozapine, clozapine-N-oxide) and inactive (glucuronides, hydroxy, and methylthio derivatives) metabolites. Clozapine is characterized by enterohepatic circulation and impaired motor-evacuatory function of the intestines. About 50% of the administered dose is excreted in the urine and up to 30% in the feces as metabolites. The therapeutic blood concentration of clozapine is 0.1–0.6 mcg/mL; toxic concentration is 0.6–1.3 mcg/mL; lethal concentration is 3 mcg/mL. It is believed that the toxic dose of clozapine exceeds 600 mg/day.

Symptoms of mild intoxication are diverse and include cerebral disorders (lethargy, drowsiness, dizziness, sometimes rigidity, tremor, ataxia) and somatovegetative disorders (dry mouth, accommodation disorders, sweating and thermoregulation disturbances; hypersalivation; tachycardia, arterial hypotension, less commonly hypertension, occasionally ECG changes; arrhythmias; gastrointestinal disorders – nausea, vomiting, constipation; biochemical abnormalities – increased serum activity of indicator liver enzymes, sometimes intrahepatic cholestasis; urinary retention). Notably, some manifestations are multidirectional (arterial hypotension or hypertension, dry mouth or salivation, etc.), which makes it impossible to attribute them to a single mechanism of drug action.

In moderate poisoning, these disorders are more pronounced. First and foremost, this applies to the state of the CNS – episodes of psychomotor agitation up to delirious clouding of consciousness, somnolence, sopor, and superficial coma are observed. Delirium usually precedes the transition of sopor into coma and manifests as confusion, visual hallucinations, and psychomotor agitation proceeding as a central anticholinergic syndrome (motor agitation is mild, limited to the bed). After the patient emerges from a coma, delirium may redevelop (secondary delirium) lasting up to 50 hours. In most cases, delirium is accompanied by hypersalivation, bronchorrhea, skin pallor, tachycardia, a tendency toward hypotension, and a tendency toward miosis.

In severe cases of poisoning, coma predominates with impaired vital functions, miosis (or normal pupils with reduced light reaction), and diminished tendon reflexes. Pronounced bronchorrhea and hypersalivation against the background of depressed consciousness lead to acute respiratory failure of the aspiration-obstructive type, which often requires immediate measures to restore airway patency. Arterial hypertension is observed more frequently than hypotension. ECG changes with QRS complex widening, typical of poisonings by tricyclic antidepressants (TCAs) which are chemically similar to clozapine, are rare, and the duration generally does not exceed 0.12–0.14 seconds. Among somatic disorders, weakened peristalsis stands out, and involuntary urination followed by urinary bladder atony is frequently observed. Toxic nephropathy and hepatopathy, accompanied by a moderate (2- to 5-fold) increase in the activity of indicator enzymes, are frequent manifestations of severe clozapine poisoning, usually detected by the end of the 1st and on the 2nd day. An increase in creatine phosphokinase (CPK) activity (5- to 20-fold), mainly due to the muscle fraction of the enzyme, is caused by impaired skeletal muscle membrane permeability resulting from moderate rhabdomyolysis. Pneumonia is one of the most frequent complications developing on days 2–3 and serves as the primary cause of death in the somatogenic stage of intoxication.

1.6.3. Clinical presentation of lithium poisoning

Acute poisoning with lithium preparations in the early stages manifests as gastrointestinal disorders – vomiting, diarrhea, and abdominal pain. In more severe cases, patients experience cardiovascular disturbances manifested by rhythm disorders (bradycardia, extrasystoles). Nonspecific ECG changes may appear – flattened or inverted T waves in chest leads, prolonged QT interval, sick sinus syndrome, and bradycardia. Neurological disorders develop later because lithium penetrates the CNS slowly. Patients develop tremor, fasciculations, hyperreflexia, choreoathetoid hyperkinesia, clonus, dysarthria, nystagmus, and ataxia. In severe cases of poisoning, consciousness is impaired – lethargy, sopor, coma, and epileptic seizures are possible. It is hypothesized that lithium impairs renal sensitivity to the antidiuretic hormone, leading to the development of nephrogenic diabetes insipidus. Long-term lithium use may cause tubulointerstitial renal damage, which can lead to acute renal failure. For this reason, in lithium poisoning, it is necessary to monitor blood electrolyte and urea levels.

1.6.4. Clinical Picture of Poisoning by Psychostimulants, ADHD Medications, and Nootropics

The clinical presentation of poisoning with the combined drug adamantylbromophenylamine + mesocarb is due to the activation of the catecholamine system. Pathological stimulation of dopamine receptors causes psychomotor agitation and hallucinations. Stimulation of peripheral and central adrenoreceptors is accompanied by hypertension, tachycardia, mydriasis, pale and clammy skin, hyperthermia, agitation, and delusional-hallucinatory symptoms. Metabolic acidosis and rhabdomyolysis may develop due to agitation, increased motor activity, tremor, and hyperthermia. Abdominal vasoconstriction may be accompanied by abdominal pain, nausea, and vomiting. The cardiotoxic effect of drugs in this group manifests as arrhythmias and myocardial ischemia. Patients on long-term therapy with psychostimulants, medications used for ADHD, and nootropics typically suffer from insomnia, aggression, impulsivity, anxiety, and suicidal ideation. Psychoses with visual and auditory hallucinations, as well as seizures, may develop.

Drugs from the group of "other psychostimulants and nootropics" have low toxicity and rarely cause severe poisoning. Excessive activation of processes in the brain leads to the depletion of metabolic resources. As a result, an effect opposite to the clinical action of the drugs is observed: drowsiness, depressed consciousness, memory impairment, irritability, and sleep disorders. Intake of high doses may irritate the gastrointestinal mucosa, causing nausea, vomiting, and abdominal pain. Hyperkinesia, headache, tremor, and seizures may occur from the nervous system.

Poisoning with herbal general tonic preparations has clinical symptoms similar to those of poisoning with psychostimulants, ADHD medications, and nootropics, but the severity of symptoms is significantly lower. The toxic effect of these drugs manifests as agitation, insomnia, tachycardia, and possible nausea, vomiting, and tremor. Strong emotional agitation is also characteristic, accompanied by possible feelings of anxiety and fear, along with motor restlessness. The patient is fussy, often experiences a sense of emptiness, loses the ability to adequately assess the environment, and has impaired capacity for calm reasoning. Since these preparations are used in the form of alcohol extracts and tinctures, the intake of large doses leads to alcohol intoxication. However, severe poisonings with general tonic preparations are generally rare.

2. Diagnostics, medical indications and contraindications for diagnostic methods

2.1 Complaints and Anamnesis

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. At the pre-hospital stage, a careful inspection of the scene is important, where various physical evidence may be found—drug packaging, suicide notes, prescriptions for potent and psychotropic substances. The obtained information must be reported by the ambulance medical personnel to the inpatient physician upon patient hospitalization and recorded in the primary medical documentation.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. The significance of anamnesis data should not be overestimated, especially in patients with suicidal poisonings who may conceal the time and type of the ingested toxic substance.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. Patient complaints in acute psychotropic substance poisoning depend on the type, dose, and duration of exposure. A feature of psychotropic poisoning is the frequent absence of complaints from the patient due to depressed consciousness, where relatives or acquaintances who notice changes in the patient's behavior, consciousness, and appearance seek medical help.

2.2 Physical Examination

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

LE – 5, GOR – C

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: assessment of the skin, mucous membranes, and pupil size is crucial for diagnosing anticholinergic syndrome, which is characterized by mydriasis, accommodation disorders, dry skin and mucous membranes, flushing, and hyperthermia, as well as for diagnosing concomitant somatic pathology or trauma.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: cardiovascular damage can result from both the direct cardiotoxic effect of the poison (primary cardiotoxic effect) and impaired mechanisms of central circulatory regulation.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. Anticholinergic syndrome is manifested by skin hyperemia and dryness, dry mouth, mydriasis, accommodation disorders (blurred near vision, inability to focus eyes at close range), tachycardia, weakened intestinal peristalsis up to the development of paresis, and urinary retention (the bladder is usually palpable). Myoclonus or choreiform movements are noted against the background of confused or depressed consciousness.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

2.3 Laboratory Diagnostics

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. When using EIA, it should be borne in mind that a negative result will always indicate the absence of the studied toxic substance in the sample, while a positive result, due to a possible false outcome (cross-reactivity), may lead to a diagnostic error, thus requiring verification by a more precise GC-MS or HPLC-MS method.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: GC-MS is an accurate method for the qualitative and quantitative determination of psychotropic substances in biological media. The method also allows for untargeted analysis, i.e., simultaneously determining a large number of various psychotropic substances. The HPLC-MS method is less accessible due to its high cost.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

2.4 Instrumental Diagnostics

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: Considering the cardiotoxic effects of the drugs, an ECG examination is performed to rule out or confirm the presence of a PCE (primary cardiotoxic effect).

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

2.5 Other Procedures

The diagnosis of acute psychotropic substance poisoning is not particularly difficult when clear anamnestic data and a typical clinical picture are present. However, such a situation is rare, and in practice, differential diagnosis with other somatic pathologies and poisoning by other neurotropic poisons is typically required.

2.5.1. Differential diagnosis of coma

In patients with acute psychotropic substance poisoning delivered in an unconscious state, the following should be ruled out:

• traumatic brain injury;

• cerebrovascular disorders (acute and chronic);

• poisoning by other neurotropic poisons (barbiturates and their derivatives, benzodiazepine derivatives, opioids, etc.);

• infectious lesions of the brain (meningitis, encephalitis of viral and bacterial etiology);

• neoplastic and tubercular brain lesions;

• comas of metabolic origin (hypoglycemic, diabetic, hepatic, uremic);

• organic mental disorders.

Comments. The presence of peripheral anticholinergic syndrome symptoms points towards poisoning with antidepressants and antipsychotics. Chemical and toxicological analysis of the patient's biological fluids assists in diagnosing acute psychotropic substance poisoning, but it is important to remember that a positive result obtained during the chemical and toxicological examination of the patient does not rule out the presence of another, more severe somatic pathology. The persistence of focal neurological symptoms, a protracted course of coma, and the lack of positive dynamics under ongoing treatment indicate traumatic brain injury or cerebrovascular disorders and serve as an indication for a comprehensive patient evaluation. It should also be borne in mind that drug poisoning can mask other somatic pathologies. Thus, when acute psychotropic substance poisoning is combined with hypoglycemia, a delayed onset of the latter's clinical picture may be observed, along with the initial absence of high muscle tone and profuse sweating. In such cases, especially in the prehospital stage, intravenous administration of 40-80 ml of 40% dextrose solution** is advisable, which provides a rapid "arousal" effect if the loss of consciousness is primarily due to low blood sugar levels [38].

2.5.2. Differential diagnosis of extrapyramidal (neuroleptic) syndrome

Poisonings with neuroleptics (antipsychotics) generally proceed with the development of extrapyramidal disorders. However, it must be remembered that extrapyramidal syndrome can accompany a number of organic diseases:

• encephalitis and meningitis;

• rigid forms of Huntington's chorea;

• true forms of Parkinson's disease;

• focal brain lesions of vascular, neoplastic, and traumatic etiology;

• Reye's syndrome with a convulsive component;

• hepatocerebral degeneration (Wilson's disease).

Drug-induced extrapyramidal disorders are characterized by acute clinical lability and are usually rapidly relieved by corrective drugs. Lumbar puncture allows for differential diagnosis with infectious and traumatic lesions. In case of a prolonged extrapyramidal syndrome, the patient must be examined by a neurologist and a psychiatrist. In most cases, neuroleptic malignant syndrome develops after taking haloperidol**, aliphatic, piperazine, and piperidine derivatives of phenothiazine, and thioxanthenes. The clinical picture of neuroleptic malignant syndrome is largely similar to serotonin syndrome (Table 5).

Table 5 – Differential diagnosis between serotonin syndrome and neuroleptic malignant syndrome [5]

Note: (–) – absent, (+) – rare, (+++) – frequent

2.5.3. Differential diagnosis of anticholinergic syndrome

When central anticholinergic syndrome develops, it is necessary to perform a differential diagnosis with other diseases and conditions accompanied by an acute alteration of consciousness with psychopathological symptoms:

- Poisoning by medicinal products with anticholinergic properties:

• atropine**;

• systemic antihistamines (diphenhydramine**);

• trihexyphenidyl**;

- Poisoning by narcotic drugs and psychotropic substances. The turnover of representatives of these groups is prohibited in the territory of the Russian Federation, as they are included in the "List of narcotic drugs, psychotropic substances and their precursors, the turnover of which is prohibited in the Russian Federation in accordance with the legislation of the Russian Federation and international treaties of the Russian Federation (List I)":

• cannabinoids (synthetic, natural);

• phencyclidines (PCP);

• cathinones;

• d-lysergide (LSD);

• illegally produced amphetamines;

• psilocybins.

- Withdrawal states with delirium;

- Endogenous mental disorders (mental illnesses).

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Maintenance and restoration of vital functions

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. In cases of aspiration-obstructive respiratory disorders, it is required to ensure the patency of the upper respiratory tract using a combitube, laryngeal mask, or laryngeal tube, perform oral cavity sanitation and suction of mucus from the upper respiratory tract. If acute respiratory failure develops, initiate mechanical ventilation (MV) using various types of mechanical ventilators, manual resuscitator bags. To stabilize hemodynamics, establishing vascular access and intravenous infusion and vasopressor therapy are indicated. [6, 21, 22].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. In severe poisonings, symptomatic treatment is essentially of a resuscitation nature. In case of vital function impairment, treatment is carried out according to the generally accepted principles in intensive care: mechanical ventilation; adrenergic and dopaminergic agents, infusion therapy to increase circulating blood volume (CBV), improve microcirculatory flow, correct water-electrolyte balance and acid-base status. Hypovolemia, as a rule, is of a relative nature, therefore correction of circulating blood volume (CBV) must be carried out under careful monitoring of central venous pressure (CVP) and hematocrit. To replenish CBV, blood substitutes and perfusion solutions are used. To improve myocardial contractility, preference is given to dopamine**. The infusion rate of dopamine** required to increase cardiac output is 2.5–10 mcg/kg/min. An increase in the administration rate up to 20 mcg/kg/min is possible. Discontinuation of dopamine** administration is carried out by gradually decreasing the infusion rate to 5 mcg/kg/min over an hour. Management of hyperthermia – physical methods (cold wraps, ice packs applied to major vessel areas, evaporative cooling) [21, 29].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. When acute respiratory failure develops during mechanical ventilation (in the absence of lung injury), use CMV (VC) or PCV (PC) as initial (starting) ventilation modes according to the following algorithm (against the background of sedation and/or muscle relaxation):

1. During CMV, set the tidal volume (Vt) equal to 6–8 ml/kg of predicted body weight (in PC mode – peak inspiratory pressure 18–20 cm H₂O); F = 8–12 breath/min; I/E ratio = 1:2; inspiratory flow rate 20–25 l/min (constant or sinusoidal flow waveform), PEEP = 3–5 cm H₂O, FiO₃ = 0.6.

2. If, against the background of the parameters specified in clause 1, chest excursion is satisfactory, respiratory sounds are audible and transmitted bilaterally upon lung auscultation, and oxygenation is sufficient (PaO₂ ≥ 80 mm Hg, SaO₂ > 95%), then the oxygen concentration in the inspiratory gas mixture is reduced to the minimum level at which SaO₃ = 96–98%.

3. If chest movements are restricted and respiratory sounds are poorly transmitted, Vt is stepwise increased by 30–50 ml (or PiP by 2–3 cm H₂O) until a "normal" level of chest excursion and transmission of respiratory sounds bilaterally upon lung auscultation are achieved. After that, FiO₂ is decreased as indicated in clause 2.

4. If hyperventilation needs to be established, change the number of machine respiratory cycles to achieve mild hyperventilation (PaCO₂ = 32–35 mm Hg) or moderate hyperventilation (PaCO₂ = 25–30 mm Hg).

5. When increasing the I/E ratio to 1:1, it is necessary to increase the inspiratory flow rate until the I/E is reduced to at least 1:1.5.

6. Perform Vt "optimization" using the Vt/Paw curve analysis.

7. Evaluate the Flow/Vt loop and the Flow/Time curve. If the Flow/Vt loop is not closed and/or the expiratory part of the Flow/Time curve does not reach the baseline by the beginning of the next breath, reduce the inspiratory time (it may be necessary to simultaneously increase the inspiratory flow rate) until a fully closed Flow/Vt loop is obtained and the expiratory flow reaches the baseline of the Flow/Time curve by the end of expiration.

8. If necessary, change the oxygen concentration in the inspiratory gas mixture (to maintain oxygenation at a sufficient level) and set an automatic "sigh" (usually 3 times per hour, 1.5 × Vt).

Taking into account the above algorithm, the most frequently used respiratory support parameters in ventilatory acute respiratory failure (ARF) are presented in Table 1.

Table 6 – Most frequently used parameters of respiratory support in ventilatory acute respiratory failure

To decide on withdrawing respiratory support, use the following main criteria: «normalization» of neurological status; the patient's ability to initiate spontaneous breathing. During the withdrawal of respiratory support, it is necessary to constantly maintain adequate oxygenation (PaO₂ = 85–100 mmHg, SaO₂ = 96–98% at FiO₂ <0.4), PaCO₂ within 35–40 mmHg, and continuously monitor the patient's level of consciousness. After complete withdrawal of mechanical breath cycles, the ventilator is switched to CPAP mode with a positive pressure level of 3–4 cm H₂O.

Particular difficulties at this stage of respiratory support may arise in the following two cases: 1) the duration of mechanical ventilation was 8 days or more; 2) the patient has apallic syndrome (vegetative coma). In such situations, the most optimal option for adapting patients to spontaneous breathing is the use of the BiPAP + MMV protocol according to the following method:

1) The lower positive pressure level (EPAP) is set within 3–4 cm H₂O, and the upper level (IPAP) at 6–8 cm H₂O.

2) The target level of mandatory minute ventilation (MMV) is determined based on 150–200 ml/kg/min of ideal body weight.

3) The IPAP level is gradually decreased (by 1 cm H₂O every 4–5 hours) down to the EPAP value.

4) Switch the ventilator to CPAP mode with a positive pressure level of 2–4 cm H₂O. If necessary, the MMV mode can be continued.

On average, the duration of the BiPAP + MMV protocol is 18–24 hours.

If the condition is stable (no increase in respiratory failure symptoms and/or neurological deficit), the patient can be extubated and completely transferred to spontaneous breathing with humidified oxygen delivery (FiO₂ = 0.3–0.35) for 3–4 hours [8, 18, 38, 41, 51, 56].

3.2. Management of Psychomotor Agitation and Seizures

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. The effect of the drug manifests quickly and, as a rule, eliminates agitation and hallucinations within a few minutes. If necessary, therapy is repeated after 3–5 hours (until the heart rate slows to 60–70 beats per minute). Overdose of the drug can lead to the development of so-called cholinergic crises, which manifest as miosis, hypersalivation, bronchorrhea, sweating, increased intestinal peristalsis with abdominal pain, bradycardia, arterial hypotension, diffuse muscle fasciculations, and sometimes seizures. A contraindication to prescribing #galantamine** is bradycardia and slowed cardiac conduction. If the QRS complex widened to more than 0.12 s, the drugs should not be administered.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. Restraint should be performed as delicately as possible, using soft, non-traumatic means (towels, sheets, cloth straps, etc.). Each limb and the shoulder girdle must be securely restrained; compression of nerve trunks and blood vessels must be avoided. The restrained patient must be constantly within the staff's field of vision. Restraint does not imply the removal of supervision, but rather requires continuous monitoring of the patient's condition. The use of patient restraint requires a mandatory record in medical documentation.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

3.3. Detoxification methods and specific therapy

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. In case of deep consciousness depression, tracheal intubation and, if necessary, initiation of mechanical ventilation are indicated prior to gastric lavage. Measures to stabilize hemodynamics and stop seizures are also required. The tube size for adults and adolescents is F36–40, and for children, F22–28. During tube insertion, the patient should be either in a sitting position or lying on the left side with the chin pressed against the chest. The correct placement of the tube is verified by injecting air with a Janet syringe (breath sounds should be audible in the stomach upon auscultation). A single water dose for a child is 10 ml/kg, up to a maximum of 250 ml. A single water dose for an adult is 250 ml. The recommended total volume of water for tube gastric lavage:

• in children under one year old – up to 1 l.

• in children aged 2-5 years – up to 3 l.

• in children aged 6-10 years – up to 4 l.

• in children older than 10 years – up to 5 l.

• in adults – up to 10 l.

Tube-free gastric lavage (inducing vomiting) is only possible if the patient is conscious and when tube gastric lavage cannot be performed [22].

• the dose of the substance is insufficient to cause significant harm to health,

• the patient has already experienced severe vomiting,

• many hours have passed since ingestion of the toxic substance and the signs of poisoning are minimal

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. Activated charcoal is most commonly used as an intestinal adsorbent. Multiple doses of activated charcoal are advisable as this increases its efficacy and interrupts the enterohepatic circulation. Colloidal silicon dioxide (per instructions), povidone (per instructions), hydrolytic lignin (per instructions), and others may also be used as intestinal adsorbents. In lithium poisoning, the use of intestinal adsorbents is impractical because they are practically not sorbed [6, 23, 24].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: The total volume of infusion therapy is 1000–1500 ml per day. In lithium poisoning, it is necessary to restore the circulating blood volume due to fluid loss through the gastrointestinal tract. To achieve this, sodium chloride** is administered at a rate 1.5–2 times higher than required for maintenance therapy, which promotes increased renal blood flow, urine output, and toxin elimination. Forced diuresis in antidepressant and neuroleptic poisoning is not justified due to the prominent binding of these drugs to plasma proteins [6, 22, 23, 24].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: For ventricular arrhythmias and QRS widening > 0.1 s, the drug of choice is #sodium bicarbonate** solution 1-2 mmol/kg (1 mL of 4% NaHCO3 contains 0.476 (~0.5) mmol); it is administered repeatedly until the blood pH reaches 7.5. After ECG normalization, it is advisable to continue administering #sodium bicarbonate** for another 12–24 hours, considering the redistribution of the toxicant from tissues [5].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: Class I antiarrhythmic drugs (Ia, Ic) – sodium channel blockers (procainamide**, propafenone**, flecainide) and Class III drugs – agents that increase action potential duration (amiodarone**, sotalol**) are contraindicated due to the risk of worsening cardiotoxicity. QT interval prolongation does not require special treatment. Correction of hypokalemia and hypomagnesemia is usually sufficient. For torsades de pointes, magnesium sulfate** is administered intravenously as an infusion, taking care to avoid arterial hypotension.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. When the toxicant remains in the enteral environment for a prolonged period due to gastrointestinal paresis and enterohepatic circulation, intestinal lavage is the method of choice in severe acute psychotropic poisoning.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. To accelerate detoxification processes via indirect electrochemical blood oxidation, a 0.06% solution of #sodium hypochlorite is used. Sodium hypochlorite solution is administered only after correction of hypoglycemia and hypokalemia at a dose of 400 mL into central veins (subclavian, jugular, femoral) at a rate of 80–90 drops per minute. In severe poisoning, #sodium hypochlorite solution is used in combination with artificial detoxification methods (hemadsorption), and the total volume of the administered solution can be doubled (either by administering two infusions of #sodium hypochlorite before hemadsorption with a 0.5–1 h interval between infusions, or by administering the second #sodium hypochlorite infusion intraoperatively within the extracorporeal circuit (along the hemadsorption line) over 20–30 minutes, as an intravenous infusion at a rate of 13 mL/min) [6].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. Hemodialysis for lithium poisoning is performed in patients with severe neurological disorders, including depressed consciousness, as well as in all patients with a lithium concentration > 4 mmol/L in acute poisoning and > 2.5 mmol/L in chronic poisoning. Furthermore, the dialysate must contain bicarbonate rather than acetate [5].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. Treatment of toxic-hypoxic encephalopathy requires adequate oxygen supply to organs and tissues. To this end, oxygen inhalation is performed at the initial stage, and mechanical ventilation in severe cases. Within the first hours after patient admission to the hospital, the therapeutic regimen should include hyperbaric oxygenation (HBO) for central nervous system disorders and substrate-action drugs based on succinic acid – meglumine sodium succinate** (10 mL/kg IV drip at a rate of 1-4.5 mL/min, course up to 11 days) or inosine+nicotinamide+riboflavin+succinic acid** (10 mL IV drip in 100 mL of 5% dextrose** solution twice daily for 5 days) [23].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. In the event of neuroleptic malignant syndrome, in addition to prescribing anticholinergics, it is necessary to ensure the fastest possible hydration via intravenous administration of plasma volume expanders and perfusion solutions, perform alkalizing therapy with sodium bicarbonate**, and manage hyperthermia using physical methods (cold wraps, ice packs applied to major vessel areas, evaporative cooling; antipyretic drugs are ineffective). Benzodiazepine derivatives should be prescribed (diazepam** 10-20 mg IM 4 times a day), especially in cases of pronounced muscle rigidity and severe catatonia. It has been suggested that benzodiazepine derivatives may directly enhance dopaminergic activity, exerting a central muscle-relaxant effect that leads to a reduction in temperature.

Specific drug therapy is prescribed – dopamine receptor agonists (dopaminergic agents), which relieve central dopamine blockade, induce muscle relaxation, and help eliminate hyperthermia: #amantadine** 100-200 mg/day IV as a 3-hour infusion, #bromocriptine** via a nasogastric tube at a total daily dose of 7.5 to 60 mg, and the direct-acting muscle relaxant dantrolene at a dose of 1-2 mg/kg [22].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

In uncomplicated cases of acute psychotropic substance poisoning, rehabilitation is not required.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

5. Prevention and Dispensary Observation

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

6. Organization of Medical Care

All victims of psychotropic drug poisoning should ideally be hospitalized in a specialized acute poisoning center. In mild cases of acute poisoning, hospitalization in an acute poisoning unit or toxicological beds of a hospital is advisable. If an acute poisoning center is not available, patients with severe poisoning and complications, especially with vital function impairment, should be hospitalized in an intensive care unit or an emergency department intensive care ward with capabilities for hemodialysis or hemadsorption, followed by transfer to an acute poisoning center or to a specialized department once their condition stabilizes.

The duration of hospitalization is determined by the severity of the poisoning. Treatment of patients is carried out in the acute poisoning unit in mild cases and averages up to 5 days; in moderate and severe poisonings, the patient is admitted to the intensive care unit until detoxification measures are completed and their condition stabilizes. The length of stay in the intensive care unit for severe uncomplicated cases is 3-5 days; for cases complicated by pneumonia, renal-hepatic insufficiency, or toxic-hypoxic encephalopathy, it is up to 10 days or more, followed by rehabilitation in the acute poisoning unit for up to 14 days or more.

Criteria for discharge from the hospital include restoration of consciousness, normalization of spontaneous breathing and hemodynamics, and normalization of homeostasis parameters.

7. Additional Information

The duration of hospitalization is determined by the severity of the poisoning.

Average duration of inpatient treatment:

1. mild severity – 1–2 bed-days;

2. moderate severity – 3–5 bed-days;

3. severe without complications – 7–14 days;

4. severe (with complications: pneumonia) – treatment duration from 14 to 24 bed-days.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Alexey N. Lodyagin – D.Sc. in Medicine, Associate Professor, Chief Freelance Toxicologist of the Northwestern Federal District, Head of the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

2. Bair V. Batsyrenov – D.Sc. in Medicine, Associate Professor, Chief Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

3. Irina A. Shikalova – Ph.D. in Medicine, Senior Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

4. Olga L. Balabanova – Ph.D. in Medicine, Senior Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

5. Andrey G. Sinenchenko – Ph.D. in Medicine, Head of the Department of Emergency Psychiatry, Narcology and Psychorehabilitation, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

6. Kuznetsov Oleg Anatolyevich – Candidate of Medical Sciences, Researcher at the Department of Clinical Toxicology, Dzhanelidze St. Petersburg Research Institute of Emergency Medicine.

7. Semyon V. Kuznetsov – Ph.D. in Medicine, Associate Professor, Leading Researcher at the Scientific and Clinical Center of Toxicology named after Academician S.N. Golikov of the Federal Medical-Biological Agency (FMBA of Russia), Senior Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

8. Rustam A. Narzikulov – D.Sc. in Medicine, Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

9. Vadim M. Teplov – D.Sc. in Medicine, Associate Professor, Head of the Inpatient Emergency Department, Professor at the Department of Emergency Medicine and Injury Surgery, First Saint Petersburg State Medical University named after Academician I.P. Pavlov.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. general practitioner (family physician);

2. psychiatrist-narcologist.

3. emergency and critical care physician;

4. forensic medical expert;

5. functional diagnostics physician;

6. anesthesiologist-intensivist;

7. infectious disease physician;

8. cardiologist;

9. clinical laboratory diagnostics physician;

10. neurologist;

11. neurosurgeon;

12. otorhinolaryngologist;

13. district general practitioner;

14. internist;

15. toxicologist;

16. transfusiologist;

17. surgeon;

18. endoscopist;

Methodology for Developing Clinical Guidelines

Working group members independently performed a systematic search and selection of publications. The search was conducted in the PubMed search engine (http://www.ncbi.nlm.nih.gov/pubmed/), the Cochrane Library (http://www.cochranelibrary.com/), the scientific electronic library eLIBRARY.ru (http://elibrary.ru/defaultx.asp), as well as in clinical trial registries: https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ctr search/search. A total of 220 publications were found, and 116 publications were selected. Based on the selected publications, thesis-recommendations were formulated and evaluated using scales for assessing levels of evidence and diagnostic methods, assessing levels of evidence (level of evidence) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions), and assessing recommendation grades (grade of recommendation) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions). (Table 3, Table 4, Table 5) Subsequently, each thesis-recommendation was thoroughly discussed at a general meeting of the working group, and a consensus was reached in all cases of disagreement.

Table 7 – Scale for assessing levels of evidence (Level of Evidence (LoE)) for diagnostic methods (diagnostic interventions)

Table 8 – Scale for assessing levels of evidence (LoE) for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 9 – Scale for assessing recommendation grades (Grades of Recommendation (GoR)) for methods of prevention, diagnosis, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Russian Ministry of Health No. 298 dated October 5, 1998, "On analytical diagnostics of narcotic drugs, psychotropic, and other toxic substances in the human body."

2. Order of the Ministry of Health and Social Development of Russia No. 40 dated January 27, 2006, "On the organization of chemical and toxicological studies in the analytical diagnostics of the presence of alcohol, narcotic drugs, psychotropic, and other toxic substances in the human body."

3. Order of the Russian Ministry of Health No. 925n dated November 30, 2012, "On approval of the procedure for providing medical care for acute chemical poisoning."

4. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On approval of criteria for assessing the quality of medical care." (In Russ.)

5. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On approval of the nomenclature of medical services."

6. Federal Law No. 489-FZ dated December 25, 2018, "On amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Protecting Citizens' Health in the Russian Federation' regarding clinical guidelines."

7. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On Approval of the Procedure and Deadlines for the Development and Revision of Clinical Guidelines, Their Standard Template, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

8. Order of the Russian Ministry of Health No. 919n dated November 15, 2012, "On approval of the Procedure for providing medical care to the adult population in the profile 'anesthesiology and intensive care'."

9. Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On approval of the list of vital and essential medicines, as well as lists of medicines for medical use and the minimum assortment of medicines required for the provision of medical care"

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

In cases of mild and moderate acute poisoning with psychotropic agents, the patient is informed about the health hazards of these toxic substances, potential complications, long-term consequences of poisoning, planned examinations (chemical-toxicological, clinical-biochemical, instrumental), and treatment (detoxification methods, pathogenetic and specific therapy). The patient (or their legal representative) signs an informed voluntary consent for the proposed scope of examination and treatment.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Poisoning Severity Score

Table specifications:

Russian title: Poisoning severity score

Original title: Poisoning severity score

Source: https://www.who.int/publications/m/item/poisoning-severity-score

Type: Rating scale

Purpose: for quantitative assessment of the severity of acute poisonings.

Contents:

Explanation: The patient's condition, according to the Poisoning Severity Scale, is assessed by the degree of organ and system damage. The occurrence of a specific symptom is checked against a scale that lists vital systems: cardiovascular, respiratory, nervous, circulatory, and gastrointestinal tract, as well as organs involved in the elimination of the toxic agent: liver and kidneys; the muscular system, local toxic effects on the body, and metabolic disorders associated with the toxicant are also evaluated. The severity grade is determined by the dominant symptom.

Appendix G2. Glasgow Coma Scale

Table specifications:

Russian name: Glasgow Coma Scale

Original name: Glasgow Coma Scale

Source: https://www.glasgowcomascale.org

Type: rating scale

Purpose: For the quantitative assessment of the severity of coma and neuropsychiatric disorders related to impaired consciousness of any etiology.

Contents:

Key:

15 points – clear consciousness

10–14 points – moderate and deep obtundation

8–10 points – stupor

6–7 points – moderate coma

4–5 points – terminal coma

3 points – brain death

Explanation: The patient's condition according to the Glasgow Coma Scale is evaluated based on three parameters, each scored in points. The points are summed. The sum of the three responses ranges from 3 (deep coma) to 15 points (conscious patient).

Appendix G3. Richmond Agitation-Sedation Scale (RASS)

Table specifications:

Russian title: Richmond Agitation-Sedation Scale

Original title: The Richmond Agitation-Sedation Scale (RASS)

Source: Sessler C.N., Gosnell M.S., Grap M.J., Brophy G.M., O’Neal P.V., Keane K.A., Tesoro E.P., Elswick R.K. The Richmond Agitation-Sedation Scale: validity and reliability in adult in-tensive care unit patients // Am. J. Respir. Crit. Care Med. – 2002. – Vol. 166, №10. – P. 1338-1344.

Type: rating scale

Purpose: To assess agitation and sedation in adult patients.

Contents:

Key (interpretation):

Patient observation:

• If alert, calm, and attentive – 0 points;

• If the patient shows signs of behavior characterized by restlessness or agitation – score from +1 to +4 points using the criteria listed above in the description;

• If the patient is drowsy, ask them in a loud voice, calling them by name, to open their eyes and look at you. Repeat this several times if necessary. Ask the patient to hold their gaze;

• If eye contact is possible with the patient and is maintained for more than 10 seconds – score -1 point;

• If eye contact is possible with the patient, but is not maintained for 10 seconds – score -2 points;

• If the patient makes any movement in response to the voice, other than eye contact – score -3 points;

• The patient does not respond to voice. Perform physical stimulation by shaking the shoulder and rubbing the sternum;

• If the patient responds with any movements to physical stimulation – score -4 points;

• If the patient does not respond to voice or physical stimulation – score -5 points.

Appendix G4. Methods of extracorporeal detoxification in acute psychotropic drug poisoning

Note: method efficacy¹ – +++ good; ++ moderate; + weak; – doubtful or absent; ¹ – extracorporeal blood detoxification is performed under comprehensive treatment and in the absence of improvement in clinical manifestations of poisoning within 6 hours from the start of inpatient treatment. Prior to its initiation, it is necessary to exclude: the overriding effect of alcohol and psychotropic substances not removable by extracorporeal detoxification methods; consciousness disorders of non-exotoxic genesis; acute neurological and neurosurgical pathology. Extracorporeal blood detoxification is performed after: repeated gastric tube lavage, enterosorption, bowel cleansing, adequate infusion therapy; registration of an electrocardiogram, general (clinical) blood count, biochemical blood test, preliminary hemostasis system screening, determination of main AB0 blood groups, and determination of the Rhesus system D antigen (Rh factor). In case of increasing poisoning symptoms and worsening of the patient's condition against the background of ongoing comprehensive treatment, extracorporeal blood detoxification is performed before the expiration of 6 hours from the start of inpatient treatment.