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Rambler's Top100


2015 year


The booklet in Russian

The human being is the only animal that can laugh, even though he has least occasions for that. 



Ernest Hemingway


Smile is a sign of good health. When eyes are laughing, everything is fine.


If our patient starts smiling, we know that our therapy is effective.


Inner comfort is a high and reliable barrier against negative external and, above all, informational impacts. A historical fact is that wounds of winners heal faster. Cold viruses more often affect people who are tired or weakened for various reasons.


Singing is also very useful. Hum to yourself while commuting, sing at home. Take care of your good mood. Your smile protects your health. All diseases are triggered by stress, and positive emotions are required to escape it. Only smiling counteracts the stress. Laughing is just the tip of the iceberg based on powerful and well-balanced hormonal and neuroimmune mechanisms.





Dotsenko A.N., M.D.,PhD, Head of the Primavera MEDICA Medical Centre named after A.P. Khokhlov











This small book consists of three parts: the first part describes paediatric diseases, and the second part is devoted to adults. These two parts are linked by the concept that all health problems of the adults originate from childhood. The third part presents the potential and benefits of neurometabolic therapy used in the Primavera MEDICA Medical Centre named after A.P. Khokhlov. This brochure is closely related to the monograph Neurochemistry of the smile. Biological fundamentals of clinical neuroscience based on the latest views of the global biomedical community (bibliography includes approximately 1000 references) and on our own experimental data and clinical experience. This book outlines current opinions on the pathogenesis of neurological, psychiatric, internal, cancer, endocrine, and other conditions in children and adults. The chapter Basics of neurometabolic therapy provides a rationale for the use of neurometabolic substances and their composites, with have been proven to be both functionally relevant in terms of therapeutic efficacy and physiologically safe.


It is crucial to understand that virtually all diseases are triggered by psychological disorders (anxiety and depressive disorders or, in other words, chronic stress and neurosis). This concept is discussed in chapter Association between anxiety and depressive disorders and neurosomatic diseases. What comes first?



The thing about this is that our body is well equipped by multiple defence mechanisms under the umbrella term systemic inflammatory neuroimmune response. This is the universal mechanism responsible for the body reaction to any environmental effect, e.g., infectious, emotional, traumatic, or climate. Although it is not so often that we catch cold or get injured, but we experience stress induced by emotions on a daily basis. We all have different stress resistance. ,However, when the


stress we are exposed to is chronic or too severe, beyond the physiological norm for each specific person, the mechanisms of systemic response start acquiring pathological features and progress towards some kind of disease



Fear and grief, that seize a man for a long time, predispose to diseases. 








In other words, attention deficit hyperactivity disorder and speech problems in children, hypertension and chronic heart disease, chronic cerebral ischaemia, multiple sclerosis, Parkinsons disease, cancer, gastrointestinal and joint diseases all these have neuroimmune basis, which was caused by stress-associated causes. And it is not only about negative, stressful emotions. Severe systemic inflammatory response can be caused even by very positive life events, such as long-awaited marriage, buying an apartment, going on a trip, waiting for the New Year holidays, anniversaries etc. Strong stress can be caused even by events which appear neutral to other people, but are of great importance for you personally.



Children endure stress particularly badly. Stress in children can be induced by broken family relations between parents or loss of one of them, lack of care or a history of abuse. In these cases, it is necessary to consider the following features.



The brain of a child is not a reduced copy of the adult human brain. Paediatric neurology is neurology of the developing brain. The developing child's brain is characterised by predominating processes of excitation and activation with apparent deficiency of inhibitory mechanisms. Therefore, even minor events can lead to hyperactivation of neuroimmune reactions.


Children feel unprotected in the outside world. The only guarantee of security for them is family, specifically parents. And if it collapses, children experience the strongest stress.


Because of their age, children cannot adequately resist the stressful situation or fight back, especially if parents are the reason. Therefore, stress in children is always much deeper and often leads to avoidant behaviour, or, in some older children, to opposing and aggressive behaviour.


Manifestations of stress itself in children are subtle, and only the consequences are visible. The developing brain and neuroimmune system in general is a complex mechanism, which is regulated by hundreds of different factors. Changes in one or more of these factors lead to changes in the syntheses of neurotransmitters, biogenic amines (serotonin, dopamine, norepinephrine), adrenal hormones (cortisol and others), thyroid and sex hormones. The immune system enters a different state, and hyperactivation of the nervous system manifests through the autonomous nervous system in many different ways.


Therefore, stress is not just a bad mood. Each stressful reaction is based on powerful neural, immune, and endocrine shifts, which lead to irreversible loss of health.



The human brain contains in itself the cause of many diseases. 






In everyday life, we view the nervous system (especially the brain), immune system, and endocrine glands as independently functioning autonomous systems. But, in fact, neural and immune regulation form a single neuroimmune system, which responds to all inner stimuli through autonomous, hormonal, immune, and autoimmune mechanisms.



Upon exposure to stress or infectious agents, cortical association areas become activated and promote the production of proinflammatory cytokines and stress-induced enzymes (iNOS, COX2 and others). Subsequently, the production of stress hormones by the hypothalamus, pituitary, adrenal glands, thyroid, and gonads (adrenocorticotropin, prolactin, oxytocin, vasopressin, cortisol, thyroxin, oestrogens, and testosterone) also increases. These events lead to the activation/inhibition imbalance in the brain and cause a proinflammatory immune surge with changes in the biogenic amine balance (serotonin, dopamine, and norepinephrine).



A cascade of further pathological events either upregulates or downregulates the expression of certain biologically active substances, mediating clinical manifestation of stress disorder (i.e., anxiety or depression).


Signs and symptoms of this condition include anxiety, impaired mood and sleep, irritability, unhealthy eating behaviour, changes in productivity and motivation, fatigue.Stress-induced symptoms include manifestations of autonomous system dysfunction: sweating, palpitations, sense of lack of air, dizziness, high or low blood pressure. Pain syndrome is also quite typical (headache, back pain, or pain in other parts of the body). Pain location may vary.


Cognitive deficits in concentration, memory, and attention are typical of stress-induced conditions (anxiety and depression) and are caused by inhibition or complete arrest of neurogenesis.

Treatment regimens are based on neurometabolic therapy, significantly improving our ability to help patients, both children and adults, with various neurological and psychiatric disorders. 


Dotsenko O.G.,M.D., neurologist 



Neurogenesis is the daily generation of new brain cells. For example, in rodents, from 30,000 to 80,000 newly formed neurons migrate into the olfactory bulbs every day, i.e., up to a third of interneurons undergo renewal every month. In the hippocampus of young rats, 250,000 new neurons appear monthly. The rate of neurogenesis is the highest in children and declines with age. However, neurogenesis continues even in the elderly. At the same time, programmed loss of neurons (physiological apoptosis) also occurs in the brain. Apoptosis eliminates damaged or bad cells. It is believed that the brain consists of more than 20 billion cells. Each year, 0.2% of these cells die through apoptosis. Therefore, there is a balance between neurogenesis and apoptosis, which is distorted as a result of inhibition or arrest of neurogenesis due to chronic stress, leading rather quickly to brain atrophy. Even a 30-minute exposure to stress is associated with atrophic changes in certain parts of the brain. Regulation of the balance between neuronal apoptosis and neurogenesis is incredibly difficult. For example, apoptotic processes are very slow in autistic children under 3, leading to overproduction of neurons and deranged brain development, but are prevailing after 3-5 years of age.


Memory mechanisms are the result of active neurogenesis. Young newly formed neurons have electrophysiological characteristics that distinguish them from mature neurons. This is why the perception of signals followed by the formation of memory traces (i.e., protein synthesis) takes place in young neurons. Working, or short-term, memory relies on the neurons formed de novo via neurogenesis.



Chronic stress leads to disturbed sleep. Sleep disorders may include difficulty falling asleep, interrupted sleep, and early or late awakening. Because of the deranged sleep architecture (specific sequence of sleep phases), it is no longer refreshing.


Brain maturation in children occurs unevenly. According to the concept of critical period, childs development involves critical periods, during which substantial developmental changes occur. There are five critical periods: postnatal, first, third and seventh years of age, and adolescence (around 13 years of age).


In children with neuroimmune disorders, timing of critical periods can get shifted or smoothed out. A period essential for speech development is from 3 to 7 years of age. At this age, chronic stress not only impairs neurogenesis, but also affects the formation of nerve pathways between different zones of the brain, which are located either nearby or distantly, including crosstalk between brain hemispheres. Anxiety or depressive conditions are accompanied by the formation of low, insufficient number of neuron processes and, therefore, low number of new connections (synapses) between nerve cells. Collectively, this leads to neural network insufficiency.


 Under chronic stress conditions, an important (if not crucial) role belongs to impaired interaction between neurons and surrounding nerve cells. This manifests as functional insufficiency of glial nerve cells (astrocytes and oligodendrocytes) and abnormal activation of microglial cells. All of these micromorphological changes are closely related to (or caused by) altered synthesis of neurotrophic factors, neuropeptides, neurohormones (including growth hormone), and endocrine hormones.


Without too much scientific detail, it should be emphasised that contemporary life with complicated interpersonal relationships, new emerging values, and a clear gap between desired and possible makes increased demands on children from the earliest age. In the past, children went to school to learn reading and writing. As of now, 6-year old kids must read and write, speak a foreign language, skate, swim, and do many other things. And this continuous emotional, psychological, and physical overstrain necessarily leads to and results in the development of chronic stress. If, above all, a family is not in harmony (Figure 1).


Chronic stress manifests itself in many ways depending on age. Developmental disorders can be diagnosed already in the first year of life, but up to the age of 3, motor and behavioural deviations are usually undifferentiated and mild.


A more accurate diagnosis of developmental disorder, whether it is attention deficit hyperactivity disorder, psycho-speech development delay, or autistic spectrum disorder, becomes possible only at about 3 years of age. 


We rarely use classic psychotropic medicines. Our neurometabolic drugs are non-inferior or even superior to them in efficacy. Moreover, they are perfectly safe. 


Korableva T.I.,M.D., child psychiatrist




Figure 1. The effects of stress on behaviour, emotions, and learning in children


Hyperactivity is the main manifestation of ADHD (attention deficit hyperactivity disorder) in children of preschool age. Excessive motor activity in the absence of sufficiently focused behavior, and emotional arousal form the hallmark of ADHD. Neurological exam detects impaired fine motor skills in 100% of cases and inaccurate coordination in more than a half. Other typical manifestations include impaired expressive speech (with hyperactivity) or receptive speech (attention deficit predominates). The peak intensity of ADHD symptoms coincides with school age (7-12 years) and becomes the main reason for social exclusion at school, in the family, and within the community. It is important to understand that learning difficulties and ADHD behaviour arise from inability to use cognitive skills in various situations rather than from mental incapacity.


Clinical manifestations of ADHD continue into adolescence in 50-80% of cases. Usually, hyperactivity decreases or disappears in teenagers, while impulsiveness and impaired attention begin to play a key role. ADHD symptoms gradually regress in 30% adolescents and persist to adulthood in 30-50%.





Anxiety and depressive disorders are difficult to recognise in childhood and, especially, in adolescence. Typical signs and symptoms include decline learning ability (up to complete refusal to attend school), lack of willingness to perform other day-to-day duties (or, more precisely, failure to perform these), inability to maintain effective relationships in the family and at school, and other forms of deviant behaviour. In addition to the classical triad of symptoms (hyperactivity, impaired attention, and


Through testing, we better understand patients condition and diagnose more accurately. 


Kuznetsova L.M.,M.D., 


PhD, psychophysiologist 

impulsivity), ADHD is characterised by twitches, hyperkinesia, headaches, opposing and defiant behaviour, anxiety disorders, enuresis, and encopresis. The intensity of these symptoms varies with age. For example, opposing and defying behaviour is observed in 32% of 5-6-year old patients and in 67% of 11-year old patients. Enuresis is present in 32% of 5-year old patients and in 17% of 11-year olds.



At the same, girls with ADHD experience anxiety disorders and obsessive fears more often than boys. Boys typically demonstrate obsessive thoughts and actions.



A combination of stuttering and twitches indicates high level of anxiety. Children with twitches usually have rituals, mannerisms, stereotypes, and other obsessive symptoms. These symptoms include nail-biting, repeated touching of clothes, tearing out hair, as well as rituals involving washing of hair and hands, eating (including food preference), elements of aggression and self-aggression. Enuresis more often accompanies different obsessions and, again, anxiety. Enuresis is caused by functional delay of brain maturation associated with the deficiency of inhibitory neurotransmitters, as well as lack of antidiuretic hormone at night.



Returning to neurogenesis as a process of neural self-renewal, increasing interneuron contacts, and brain maturation, it should be noted that delay or cessation of neurogenesis is one of the main consequences of chronic stress in children. Restoration of neurogenesis can be promoted by the so-called enriched environment, which represents a combination of favourable emotional atmosphere, physical activity, and diverse experiences (e.g., travelling). Neurogenesis can also be restored by normalization of biogenic amine synthesis in the brain structures. Serotonin is the first in this line.



Generally, the key manifestations of emotional, behavioural, and motor disorders in children, including hyperactivity, impulsiveness, twitches, obsessions, and fears, reflect excessive excitation of individual brain regions, when their increased neuronal activity is insufficiently blocked.



The principle control of inhibitory mechanisms in brain structures is mediated by serotonin and noradrenalin neurotransmitter systems. Impaired mutual regulation within this system is responsible for multiple disorders characterized by deficient inhibitory mechanisms, and emotion-induced cortical activation in the absence of controlling GABA effects is the constant trigger (GABA is one of the main inhibitory brain chemicals that put the brakes on brain activity when needed).



Much of the above is relevant to the autism spectrum disorders. It is almost universally accepted that autism manifestations are a consequence of systemic disorders of brain development, starting from the earliest stages.



It was convincingly shown that the volume of the brain in these disorders increases from the first to the fourth year of life due to the lack of elimination of neurons via apoptosis. Up to 40% of neurons are destroyed in normally developing children of 1.5-2 years, resulting in removal of the surplus cells and non-functioning neural connections.




In autistic children of early age, apoptosis is incomplete, and the excess of neuroglia cells hampers further development of the brain.



In contrast, autistic children aged 4-10 years demonstrate rapid decrease in grey and white brain matter formation and, consequently, impaired neurogenesis. The development of the brain is impaired in autistic children during infancy and preschool age, i.e., when connections between different cortical areas underlying the formation of perception, thinking, and speech are formed.



Treatment of most diseases takes a long time. Therefore, it is very important to consider, beyond efficacy, the safety of neurometabolic drugs. This is especially important for children. 


 Ivanushkina I.Yu.M.D.,, psychiatrist





The abovementioned facts suggest that increased local activity in the brain could cause impairment in coordination between its various parts. With regard to excessive activation of certain functional areas, it may be associated with deficient communication between the brain structures responsible for regulation (inhibition in this case). Consequently, a syndrome of dissociation between functional cortical and subcortical structures develops. This is particularly true in the context of such complex and multifaceted brain function as speech. On one hand, research in this area has substantiated the notion that speech disorders can be also due to developmental disorders in the brain regions that are far from the well-known speech centres (Wernickes and Broca areas). On the other hand, the mechanisms of brain neuroplasticity offer replacement of affected cortical functions by engaging new areas through increase of horizontal connections between neurons. It is known that anatomical connections between neurons stretch for far wider area than their area of functional activity. Many of these connections are in the state of tonic inhibition. Removal of inhibition activates these silent connections and engages them in the activity of the functional zone. Another mechanism of brain plasticity is associated with the phenomena of long-term potentation or depression, which form the basis for increase or decrease in the transmission of nerve impulses. An important component is the activation of neurogenesis and formation of young neurons with low threshold of membrane excitability, as well as branching of neurons with the formation of new contacts between those. An intact hemisphere also plays an important role in the recovery of the lost function.



Autism manifestations have been shown to correlate with brain neurochemistry, i.e., impaired turnover of serotonin, noradrenalin, dopamine, cholinergic deficiency, and reduced synthesis of oxytocin.



A number of studies have been given to the role of biogenic amines in the pathogenesis of autism spectrum disorders. Clinical and genetic studies have shown that development of such disorders as altered mood, social phobia, anxiety disorders, obsessive thoughts and actions, is associated with the expression of genes involved in the regulation of serotonin synthesis and action. Serotonin plays the key role in the formation of different types of behaviour and in such processes as emotional perception, behavioural inhibition, appetite, aggression, sleep, mood, social contacts, and hormone production.



Beyond the role of neural transmission mediator, serotonin has strong effects on the processes of neurogenesis, brain maturation, and formation of contacts between nerve cells in the developing brain.


In the central nervous system, serotonin often functions as a brake, but its end effects are complex and defined by a specific subtype of serotonin receptor stimulated (from a total of 7 subtypes). The inhibitory action of serotonin becomes crucial during the most important period of brain development in early childhood, when the principal inhibitory system (GABAergic) is mainly activating, rather than inhibiting.


During systemic neuroimmune response induced by injury, stress, or infection, the rate of tryptophan transformation to toxic kinurenins and even more toxic quinolic acid drastically increases (Figure 2, processes 1-a and 1-b). In fact, exogenous tryptophan was reported to increase significantly the severity of autistic behaviour. This is entirely understandable, since it further enhances the already activated kinurenin pathway of tryptophan degradation and activates neuroinflammation. At the same time, through the upregulated kinurenin pathway of tryptophan degradation, the activity of the serotonin pathway is reduced and the production of serotonin (Figure 2, process 2) and melatonin (nocturnal hormone with potent antioxidant activity) inhibited, because serotonin is the only source for melatonin synthesis (Figure 2, process 3).


There is no doubt that both innate and adaptive immune response mechanisms are involved in the pathogenesis of autistic disorders. The presence of neuroimmune inflammation in autism can be confirmed by detection of increased levels of relevant immunological markers.


Figure 2. Tryptophan conversion pathway



Autism in children is primarily associated with the activation of innate immunity. Mechanisms of adaptive immunity (production of antibodies against auto-neuroantigens) are usually enabled in more severe pathology, i.e., atypical autism in children, suggesting the autoimmune origin of this condition.


Clinical neurologic deficit associated with impaired brain development reflects the functional activity of the whole brain, including adaptive neuroplasticity, rather than any damage in the brain structures. Among the predictors of adaptive capacity and recovery of the brain, patients age plays an essential role. Up to 90% of children with psychoneurological disorders develop normally throughout infancy. Consequently, the immature brain copes better with injuries and has greater potential for neuronal plasticity. Therefore, therapeutic and correctional rehabilitation should start as soon as possible in order to use for maximum the physiological benefit of the critical periods of development at the age of 1, 3, and 7 years.





There is an opinion that autism and developmental delay can be reliably suspected only at the age of 2-3 years. But this is not true. Today, experts have sufficient knowledge and experience to take notice of multiple symptoms of autism spectrumdisorder already within the first three months of life. During this period, infants can be generally anxious, show increased sensitivity to sound, light, and touch (do not like to be held in someones arms, bend when being held), intermittent (immature) sleep, altered feeding behaviour, including early cessation of breastfeeding and holding food in the mouth or swallowing of non-chewed food at later age. When not tracking objects, infants can demonstrate enchanted view, staring into space, and staring into themselves. Later, at the age of 4-6 months, particular attention should be drawn to squeezing of three most lateral fingers (3-5) in a fist, without pressing the thumb and index into the palm. This causes a split manner of capturing subjects only with the thumb and index. Subsequently, because of incomplete carpal capture, the child will prefer small toys, because they are more convenient to hold with two fingers. Also it is difficult for them to hold a spoon or bottle. Extreme bending of toes, which subsequently leads to walking on tiptoes and in a circle, is also possible. Attention should be paid to the stereotyped (repetitive) flapping of hands, resembling the flapping of wings. Speech development also appears delayed, and this delay has its specifics.






We do not address the symptoms of autistic disorders in children above1-1.5 years, because they are obvious to parents and quite specific.



Thus, the combination of motor symptoms, behavioural traits, delay in speech development and other symptoms of impaired development become the reason for referral to medical specialists. In this case, if rehabilitation coincides with the critical period, a change in childs development appears more justified.



If active therapy and correction are initiated at the age of 2-3 years, the development can be stimulated at this critical period, although it is delayed until the age of 3.5-4 years, and the state of the child may improve. The same applies to speech development, because it begins during the first year of life and basically ends in the critical period at 7 years of age.



During this period, the brain potential for speech development is particularly prominent. This is completely applicable to the activation of neuroplasticity to compensate for functional insufficiency in children with cerebral palsy (CP) and periventricular cerebral injury of hypoxic-ischaemic or haemorrhagic nature. Periventricular brain damage caused by hypoxia resulting from utero-placental insufficiency, asphyxia at birth, postnatal respiratory distress, and infectious-inflammatory factors has been demonstrated to be a cause of mental and motor impairment.


Intrauterine infection and prolonged time between membrane rupture and delivery are believed to be the leading cause of damage to periventricular brain structures.



One of the advantages of neurometabolic therapy is that we can see the first results very quickly, literally at the next patients visit 5-7 days later.


Gorokhova E.I.,M.D., paediatric neurologist




Damage to the brain structures is a cause of different types of cerebral palsy, depending on its form and localisation. However, the developing impairment of neuronal organisation, myelinisation, and formation of projection interzonal connections in CP patients leads to delay in brain development, which causes mental, motor, and speech delay.



Childs health is largely determined by mothers physical and mental state at pregnancy. Mothers anxiety or depressive disorder during pregnancy is associated with a depression-like state in her newborn (continuous cry, hypodynamia, and pathological reflexes). The impact of maternal anxiety during pregnancy on the development of the child has been evaluated in several interesting studies. Anxiety at 18 weeks of pregnancy contributes to the development of behavioural and emotional disorders, but only in girls. Anxiety at 12-22 weeks of pregnancy is associated with ADHD in 8-9 year olds, especially boys. Anxiety at 32 weeks of pregnancy increases the risk of ADHD at the age of 4-8 years almost two-fold.



It is known that anxiety and depressive disorders significantly increase the risk of preterm birth.



It is obvious that maternal emotional and mental state during pregnancy plays a substantial role in the foetus development and pregnancy course, and, to a large extent, determines the characteristics of future delivery and development of the child. However, depression or anxiety in pregnant women are underdiagnosed. In the United States , gynaecologists do not diagnose mental disorders in 77% of patients. In Australia , 50% of obstetricians do not even ask their patients about symptoms of depression.



There is a growing body of evidence for the involvement of the maternal immune and hormonal systems in the regulation of embryonic development. Deviation of female immune or hormonal parameters from the normal range increases the risk of birth of an unhealthy child with nervous system pathology. Several years later, these children show delay in psychomotor development, epileptiform brain activity, ADHD or autism. It is now believed that maternal, but not paternal, immunity within the mother-child pair plays a matrix role in the formation of the childs immune status. Thus, each child has its own features of immune reactions, largely copied from the immune status of the mother. In turn, the number and extent of stressful, anxious, and depressive episodes in her life determine the mothers immune status. That is why it is commonly considered among general public that it is necessary to give birth early, before a burden of life problems starts having a significant impact upon woman's health.



Depression during pregnancy is regarded as a risk factor for intranatal emotional distress and postnatal depression. Approximately in 1/3 of pregnant women suffering from depression, this condition continues into the postpartum period. If the mother is suffering from depression, her harmonious nonverbal relationship with the child becomes disturbed. Anxiety, fears, and other negative emotions induced by a newborn baby adversely affect his/her adaptation and development.



Stress-induced anxiety-depressive disorder as the basis for development of neurological, mental, somatic, endocrine, and oncological diseases


According to the literature, up to 50% of the world population suffer from different forms of anxiety and depressive disorders. If latent subclinical forms of this disease are


taken into account, this condition is present in 76% of the population. According to the World Health Organization, depression can become the most prevalent condition by 2020, exceeding the prevalence of cardiovascular diseases.



Keeping patients spirits up by happiness and communication with good people should be considered a potent treatment


Avicenna (Ibn Sina)




It should be mentioned that diagnostic stigma is very important for the patient. The patient can accept it (if he/she believes that the diagnosis matches the existing condition), or find it offensive (if you are using a psychiatric term).



The same combination of symptoms can be termed differently depending on the doctors speciality, i.e., neurologist, psychiatrist, or general practice physicians. You just need to understand that chronic stress, anxiety, vegeto-vascular dystonia, and somatoform dysfunction are individual fragments of the common state entitled anxiety and depressive disorder, when a patients mental status is underestimated. Moreover, those physicians who are not qualified in the diagnosis and therapy of mental disorders can treat anxiety as trivial nervousness or difficult character. They misdiagnose various forms of depression in 50-80% of cases. Actually, such diagnoses as restless legs syndrome, irritable bowel syndrome, irritable bladder, burnout syndrome (or managers syndrome) that have become trendy nowadays, are also symptoms of anxiety-depressive disorder.



Anxiety-depressive disorders can be characterised by mood changes, irritability, anxiety, but also chronic fatigue, pain of different localisation (headaches, migraines, back pain, joint and limb pain), changing eating behaviour (in either direction), hormonal changes, and manifestation of the autonomous nervous system symptoms, e.g., vertigo, low or high blood pressure, palpitations, sense of lack of air, sweating and others. It is not surprising that patients undergo unnecessary diagnostic investigation, and changes in the eating behaviour are being treated by a dietician or endocrinologist, and hormone therapy is prescribed by a gynaecologist for menstrual cycle disorders. Patients with other symptoms visit rheumatologists, cardiologists, gastroenterologists, surgeons, who begin to treat individual symptoms of this complex condition.



This treatment results in little effect or no effect whatsoever, but side effects from potent medications are always present.



There is mounting evidence that depression, like no other mental disorder, is both somatic and somato-neurological pathology. Somatisation, the conversion of mental experiences or states into bodily symptoms, including vegetative, metabolic, neuroendocrine, and immune disorders, is a natural manifestation of depression, that is to say, its essence.


 In recent years, our mood is increasingly viewed upon as an adaptive reaction to environmental changes, while severe and prolonged emotional reactions are considered to be the result of psychoemotional stress leading to disadaptation, i.e., depressive disorders. Mood disorders primarily lead to behavioural changes.


Development of excessive petulance and vulnerability shapes the avoidant behaviour model or, on the contrary, results in pronounced irritability, short temper, and aggression.




A patient needs to be treated with regards to his/her temperament... Of which there are four types.


The first one is the choleric type - a fast, strong, unbalanced temper.


The second one is the sanguine type - heavy, changeable, but balanced.


The third one is the phlegmatic type - strong, calm, mild and smooth, inert.


The fourth one is the melancholic type - unstable, weak, and prone to melancholy and distraction.





It can be assumed that stress-induced suppression of neurogenesis separates our emotions from negative external effects, thereby protecting the body, but at the same time contributes to the development of depressive disorders.


It turns out that stress-induced suppression of neurogenesis is the cause of anxiety-depressive disorders. Conversely, the formation of new neurons due to successful treatment is the prerequisite for full recovery.


The effects of stress factors on humans are much stronger due to more advanced mental state compared to other representatives of the animal kingdom, reacting to external stimuli mainly via evolution-driven mechanisms. Stress, infections, injuries induce the same nonspecific defence mechanism, that is, systemic neuroimmune response of the body. In the modern world, stress exerts its negative effects on us more often than infections and injuries, i.e., almost every day (Figure 3).



Anxiety-depressive-neurotic disorders are triggered by long-term or short-term, but strong negative emotional stress, which causes hyperactivation of associative cortex.



The main body structures involved in the stress response are the hypothalamus, pituitary gland, brain stem nuclei, which produce biogenic amines, adrenals, and autonomous nervous system. The hypothalamus, along with the pituitary gland, represents the supreme division of the neuro-immuno-endocrine system, which coordinates endocrine regulation, immune status, and functions of the autonomous nervous system. Control is implemented via the autonomous nervous system, which innervates the internal organs and blood vessels, as well as via the powerful hormonal axes: hypothalamic-pituitary-suprarenal axis, hypothalamic-pituitary-thyroid axis, hypothalamic-pituitary-gonad axis, and hypothalamic-thymic axis. These axes mediate stress-induced changes in the production of adrenal, thyroid, and sex hormones. Prolonged gland stimulation leads to their depletion and development of hypothyroidism, and to reproductive disorders in men and women. Thymus reactions to stress manifest themselves as a change in many immune processes.



Any stressful reaction is accompanied by oxidative stress. It increases production of reactive oxygen and nitrogen species without proper balancing action of the antioxidant defence mechanisms. This triggers a cascade of events leading to the production of charged oxygen and nitrogen molecules. These molecules exert deleterious effects on the cell structures (including the nucleus) followed by their death.



In anxiety and depression, hormonal imbalance is closely associated with impairment of biogenic amine production. Biogenic amines are involved in behavioural (aggression, anxiety, phobias) and cognitive (memory, concentration, thinking) functions, and affect the motor and sensory (including the feeling of pain) systems, hormone production, and biological rhythms. Among myriads of nerve cells in the brain, only a few (tens of thousands) are aminergic. Their death dramatically reduces synthesis of serotonin, dopamine, and norepinephrine.



In the triad of biogenic amines, serotonin plays a special role. Serotonin regulates the mood, behaviour, basic physiological functions, motory control, appetite and eating behaviour, sleep (slow-wave phase), body temperature, and pain sensitivity. Serotonin deficiency leads to anxiety and panic attacks, obsessive thoughts and movements, ravenous appetite, sleep disorders, fatigue, impaired memory, pain of different localisation (including daily headaches), and migraine.



Figure 3. Development of core symptoms of anxiety and depressive disorders




 Figure 4. Stress as a basis for the development of various diseases

Noradrenalin generates mood, attention, and psychomotor activity.


Dopamine causes aggressive behaviour (if there is a lack of serotonin) and is involved in the motory control.


If serotonin deficiency is present, the production of melatonin is reduced. Melatonin is formed from serotonin during the night, has strong antioxidant effects, and set the biological (circadian) rhythm of various body systems. Desynchronisation of links between sleep, mood, and other physiological cycles cause sleep disorder, excessive sleepiness, and fatigue during waking hours, as well as low mood.


Sleep disturbance in affective disorders includes difficulties with falling asleep, frequent awakening at night, and waking up early in the morning. Mood disorders with predominance of asthenia and sadness are characterised by going to bed and waking up early, and falling asleep and waking up late in the case of anxiety symptoms. Elderly patients with depression usually have intermittent sleep and wake up early, while younger women more typically demonstrate hypersomnia (excessive sleepiness).






During sleep, the brain oxygen consumption is reduced. Under these conditions of relative hypoxia, the processes of neurogenesis and subsequent maturation of nerve cells can occur. Therefore, renewal of brain cells (at night) and its functional activity (at day) are spaced out in time. During sleep, secretion of many biologically active substances, including human growth hormone (which is important for children), increases. It is also the nocturnal synthesis of melatonin, the strongest antioxidant that neutralises toxic products accumulated during the day.








Certainly, sleep is absolutely necessary for growth, development, memory, as well as correction of metabolic disorders acquired through daily activities.


The best sleep is deep sleep. Anxious, nervous, intermittent sleep cannot be called healthy.


Avicenna (Ibn Sina)




Thus, chronic stress leads to powerful immune, endocrine, and neurochemical changes that result in neurodegenerative, demyelinating, hormonal, somatic, and oncological diseases (Figure 4). Neuroimmune systemic response to stress and virus infection is the basis for the development of demyelinating and neurodegenerative diseases.


Multiple sclerosis (a form of demyelinating disease) is the most common demyelinating disease. Symptoms of multiple sclerosis, i.e., anxiety, depression, chronic fatigue, and cognitive dysfunction, are associated with activation of the neuroimmune system. Studies into association between psychogenic situations and development (as well as subsequent relapses) of multiple sclerosis suggest that the onset of this disease or its exacerbation is almost always preceded with periods of stress and anxiety. As for the seasonal relapses occurring in the autumn or spring, they are most probably associated with depressive disorders and infectious diseases whose incidence increases dramatically during these seasons.



Similar neuroinflammatory process can also underlie neurodegenerative diseases, such as Parkinson's disease, which is associated with cell death within substantia nigra, a dopaminergic cell cluster of the brain.



Fatigue (chronic fatigue) syndrome is a manifestation of anxiety-depressive disorder. It accompanies demyelinising, autoimmune, neurodegenerative, and somatic diseases.



Fatigue syndrome includes physical and mental asthenia, along with decreased activity and motivation. The severity of fatigue correlates with the severity of the



neuropsychiatric disorder, and aggravation of the former may precede exacerbation of the latter. Immune components play an important role in the development of chronic fatigue syndrome.



If someone gets tired for no reason, without tiring work, it shows that illness is coming.





Coronary and cerebral vascular diseases. Humans react to emotional and psychotraumatic events by activating the inflammatory and immune processes, which are directly coupled with blood circulation. Chronic cerebral and cardiac ischaemia is based on the systemic inflammatory process, which is always closely linked with alterations of the inner lining of the blood vessels (endothelium) and atherosclerosis. Under these circumstances, the latter acquires features of immune inflammation. Currently, atherosclerosis is considered to be essentially a chronic inflammatory disorder. Specifically, it is a manifestation of systemic and vascular inflammatory response of the body that is caused by oxidative stress and changes in lipid profile. Recurring psychotraumatic events, which are not blocked by neurochemical inhibitory mechanisms (serotonin or gamma-aminobutyric acid deficiency), lead to development of chronic ischaemia via activation of the autonomous nervous system and neuroendocrine axes. Chronic brain ischaemia accompanies anxiety-depressive disorders and headaches, sleep disturbances, increased fatigue and other autonomous, emotional and endocrine disorders. Anxious-depressive mechanisms are also involved in the development of coronary heart disease, hypertension or hypotension, and chronic heart failure. Cardiac arrhythmia arising from emotional imbalance is also well known.



PAIN. Pain, both acute and chronic, is not a separate disease. The biological function of pain is to signal a trouble in the body. In a large study (540 patients with depression), nonspecific pain of different localisation occurred in 532 (98.5%) patients. One of the conclusions of this study was that untreated depression can be an integral stage in the transformation of nonspecific pain to chronic pain. This also applies to episodic headache and to migraine. Basing on the study into chronic pain syndrome, we understood that a major role in its development belongs to anxious-depressive state (except for cases of analgesic abuse). Other common partners of depression include panic and other anxiety disorders. It turns out that anxiety is usually preceded by migraines, while depression occurs later. Given the shared mechanism of migraine and panic attacks, both conditions related to the so-called paroxysmal brain, and their close link with anxiety disorders, there could be a triple association between migraines, panic attacks, and anxiety with the key role attributed to depression. Thus, the combination of anxiety-depressive disorders and pain syndromes including migraine can be not just a coincidence. As for panic disorder, this pathology is studied both by neurologists and psychiatrists. In neurology, panic disorder is viewed as an autonomous crisis, and in psychiatry, as anxiety-phobic state, emphasising the predominance of emotional-affective symptoms, e.g., fear and anxiety.



MEMORY. Typical complaints in anxious-depressive disorders are memory


impairment, decreased learning ability and motivation, and, as a result, reduced cognitive performance. Cognitive functions, especially memory and learning, are associated with the formation of new nerve cells (neurogenesis) in the hippocampus (Latin for seahorse).



The memory cannot be improved - it can be restored.




How we see the problem in the Primavera MEDICA?




Hippocampus translates short-term memory into long-term memory and provides preservation of long-term memory until it is fully consolidated in the cortex.


The newly formed neurons have properties and functions that differ from mature nerve cells. Immature cells are characterised by increased excitability, capacity for long-term activation, and reduced sensitivity threshold. Before final maturation, neurons function as integrators of memory trace. New neurons are required to reflect on events occurring in the particular time of someone's life. A strong link between mechanisms of neurogenesis and emotional perception of events has been proved.



Factors that stimulate neurogenesis also promote good memory, and, conversely, inhibition of neurogenesis impairs educational potential. Chronic stress slows down or stops neurogenesis. Neurogenesis is favoured by positive environment, which means emotional comfort, appropriate level of physical activity, and adequate serotonin levels.



Thus, it can be argued that systemic inflammatory response induced by psychogenic factors and involving pathophysiological neuroimmunoendocrine mechanisms is a nonspecific universal reaction to a variety of environmental factors. Clinically, systemic response can manifest as various combinations of syndromes (with prevalence of affective disorders, various autonomous-somatic conditions, or with greater involvement of immune and autoimmune mechanisms), depending on the neuroplasticity and immunoreactivity of the body (Figure 4). However, the main neurochemical, immunological, and endocrine markers can be found in all diseases, regardless of the presence or prevalence of one or another clinical syndrome. Their dynamic changes are primarily determined by the stage and direction of the pathological process.



We all should understand that nervousness, petulance, grumpiness, vulnerability, anxiety, reluctance to do something and many other not very pleasant character traits are not inherent to human character. They point out towards symptoms of the disease, known as anxiety-depressive disorder. And there is only one solution here, that is, appropriate treatment. Exercising willpower muscles will not help in these cases. Moreover, if one person in the family is in the state of chronic stress, neurotic reactions spread to the entire family by the rule of emotional resonance. This means that it is necessary to treat the entire family. And one more thing. People, both children and adults, inherently do not have laziness. There are no lazy people. If a child does not want to do homework or to go to school, or an adult does not want to get up from the couch or sleeps a lot, this is a reason to see a specialist. It is almost for sure that the doctor will find other symptoms of anxiety-depressive condition.



It is not unrare that a patient presents with multiple somatic complaints at the first visit (lack of air, rapid heartbeat, blood pressure, fatigue, etc.) and says that the state has changed for better during the second visit, 10-12 days later. Only at this point, he/she understands that emotional discomfort, anxiety, etc. experienced for a long time was not a normal life.



Basics and benefits of neurometabolic therapy



Pathogenetic mechanisms underlying depressive, demyelinating,and neurodegenerative diseases are non-specific and universal. Depression can develop into any of the above or become a concomitant condition, which complicates the course of underlying disease. Neuroimmune disorders may be not only a cause, but also a consequence of depression. In this way, the mechanisms of depression interface psychoneurological disorders and internal medicine. In any case, a unified approach to development of treatment strategy for these diseases is required.



This section discusses the potential for clinical application and therapeutic efficacy of neurometabolic substances, which are well known in neurochemistry and pharmacology, but are not commonly used clinically.



This therapy cannot be short-term. As such, it uses only those drugs that have minimal to no side effects, meaning they should be either natural endogenous substances or their derivatives and precursors (predecessors). As natural participants of metabolic processes, these compounds are more physiological, their action is plausible and understandable, hence, predictable, and, moreover, safe in a wide therapeutic range.



The directions of therapeutic effects and pathophysiological targets are well known and include antioxidant protection, neuroprotection, support of cellular bioenergetics; restoration of integrity of the blood-brain barrier; combating endothelial dysfunction, neuronal hyperactivity, and deranged neuroglia interaction; normalisation of activation-inhibition balance, primarily glutamate-GABA, interactions and balance of biogenic amines, and correction of pathologically modified systemic neuroimmune response, etc.



It is unlikely that neuropeptides, neurotrophic factors, neurohormones, and other large molecules can exert pharmacological effects on gene expression, and there are several reasons for that. First, active effector molecules such as active peptides and monomolecular compounds (glutamate, GABA, serotonin, taurine, etc.) are practically unable to cross the blood-brain barrier. Second, protein molecules, including those of small size that consist of 10-15 amino acids, are readily degraded with any route of administration. Therefore, their effects are short-term, and dose escalation results in serious side reactions. Third, exogenous peptide molecules induce autoimmune response, i.e., antibody production against these molecules.



The only way to overcome these obstacles left for us by the nature (and successfully employed by it) is to use the precursors (predecessors) or monomolecular derivatives of biologically active molecules.



These substances are able to cross cell barriers. They become actively involved in the metabolic processes and act as universal up/down-regulators of metabolic reactions.



Using such regulators, even orally, one can modulate the activity of neurons and neuroplasticity pathways, and, in the long run, control gene expression.



The first lesson of wisdom is to follow nature.





State-of-the-art therapy should rely on the use of immediate precursors of neurotransmitters complemented with neuromodulators, enzymes and cofactors, and orthomolecular active substances.



As already discussed in previous sections, many pathological processes are triggered by the stress causing hyperactivation of the limbic system and primarily of its hypothalamic-pituitary component. Certainly, this does not apply to infectious, toxic, injury-induced, or other conditions. In any case, however, a universal neuro-immuno-endocrine systemic response is developed regardless of the exogenous factor.



Normalisation of cerebral and peripheral serotonin and catecholamine levels.For the last four decades, the monoamine hypothesis has dominated our understanding of the pathogenesis of anxiety and depression. According to this concept, the central part in depression is played by serotonin, noradrenaline, and, perhaps, dopamine deficiency. In the official medicine, the main role in the treatment of anxiety and depression belongs to antidepressants, which restore the balance of monoamine systems in the brain, especially serotonin and norepinephrine, and functioning of their receptors.



Antidepressants have been shown to increase antioxidant levels, to reduce neuroinflammatory activation, to inhibit proinflammatory cytokine production, to reduce activity of the hypothalamic-pituitary-adrenal axis, and to stimulate the synthesis of neurotrophic factors and growth hormone, which improve processes in the nerve tissue. This restores neurogenesis and decreases apoptosis. Collectively, these effects provide anti-anxiety, sedative, analgesic, and anti-phobic action, and also reduce physical and cognitive fatigability.



However, antidepressants of all known 9 groups have significant side effects, including stimulation of anxiety, sleep disturbances, gastrointestinal disturbances, headaches, tremor, sexual dysfunction, and development of serotonin syndrome. The delay between start of therapy and onset of its therapeutic action, which is usually 3 to 4 weeks, as well as the rebound phenomenon occurring upon discontinuation of antidepressants are also very disadvantageous. Therefore, 16-30% of patients stop taking antidepressants due to side effects, and about 30% do not notice any effect of therapy. Remission is achieved in less than 50% of patients.



The fact is that action of the known antidepressants is based on the blockage or activation of serotonin turnover regulators. These regulators operate within the regions of serotonin synthesis, i.e., in the brain nuclei and the intestinal mucosa, and in serotonin deposits (mainly, in platelets). Thus, exogenous antidepressants affect the whole brain, rather than any targeted area, and, in addition, derange peripheral



Neurometabolic therapy allows me to treat more effectively non-psychotic mental disorders, including substance abuse. 


Novikov S.P.,M.D., psychiatrist.


serotonin turnover in the plasma-platelet interface, resulting in adverse reactions and rebound syndrome.The main characteristics of the ideal antidepressant include quick onset of therapeutic effect, safety, lack of side effects, and good tolerability during long-term maintenance therapy. Intake of serotonin precursors allows avoiding side effects and complications because of their physiological nature. They start acting 30-40 minutes after the intake. Such precursors are well tolerated and can be combined with any drugs.



Given the rapid onset of anti-anxiety and sedative effects, i.e., 30 to 40 minutes following administration of serotonin precursors, their use appears promising in acute psychoemotional situations (or before them) to increase stress resistance and prevent the consequences of such reactions.


Improvement of serotonin synthesis in the brain leads to activation of neurogenesis and affects gene expression. An increase in the serotonin level has been proven to be the first specific way to modify neurogenesis (both in children and adults) through direct exogenous regulation.


Exogenously administered serotonin precursors also support its physiological synthesis. In this way, the rate of serotonin synthesis is determined by the body itself, and it takes place only in those tissues where it is required. When selecting the type of serotonin precursor, it must be taken into account that additional intake of tryptophan is undesirable, because it can lead to even greater activation of kinurenin degradation pathway (Figure 2) with increased adverse effects of kinurenins and neuroinflammatory reactions.



In recent years, much attention has been given to therapeutic potential of melatonin and its synthetic analogues. There is no doubt that melatonin has powerful antioxidant activity and significantly affects the bodys biological rhythms. However, when using exogenous melatonin or activators of melatonin receptors, its suppressive effects on the secretion of sex hormones, antidiuretic hormone, corticosteroids, and mineralocorticoid, and stimulatory effect on prolactin production should be taken into account. Special caution should be exercised in children, as there is the risk of growth and puberty delay. Melatonin levels can be increased in a more physiological way via administration of serotonin precursors rather than exogenous melatonin. This way of melatonin normalization (through increased levels of serotonin, which acts as melatonin precursor) (Figure 2, reaction 3) is more physiological, effective, and safe for the body. Most importantly, the body itself in this case regulates the rate of melatonin production.



Potential of neurometabolic therapy to counteract cortical hyperactivation. Activation-inhibitory balance. Activation-inhibitory balance becomes altered because of hyper-stimulation of activation systems and insufficient inhibitory mechanisms. The latter is prerequisite for this condition. Therefore, the altered balance can be restored in two ways:




1) suppression of hyperactivation;


2) stimulation of inhibitory nervous mechanisms.



According to the approved clinical guidelines, the activity of stimulatory amino acids, glutamic and asparagic, can be suppressed by agents blocking potential-dependent channels, receptors, and neurotransmitter transporters. There is a great variety of such drugs, and all of them are listed in books and manuals. However, these agents designed to block calcium entry into cells also cause well-known side effects. Furthermore, calcium activation becomes impaired not only in all brain structures, but also in the spinal cord and outside the central nervous system, i.e., in the peripheral tissues, including blood immune cells. As a result, we see a generalized disruption of neurotransmission and immune processes with impaired production of vital substances, hormones, and neurotrophic factors.



Neurometabolic therapy relies on the use of more functional restrictors of activation signals. The most physiological solution is the one using natural blockers of activation receptors in neurons, i.e., magnesium and zinc. Magnesium is a natural insulating material for nerve impulse conduction. Stress resistance is higher in individuals with sufficient magnesium pool. Low magnesium is common among individuals subject to chronic stress. Magnesium deficiency is found in 70% children with ADHD and in adults with cerebrovascular and other diseases. Adolescents with deviant forms of behaviour show deeper levels of magnesium deficiency. Some researchers believe that high doses of magnesium (in combination with vitamin B6) are fundamental for effective treatment of infantile autism.



Low zinc levels can be found in the blood of patients with anxious-depressive conditions. Zinc is known to be essential for brain development and neurogenesis.



Pharmaceutical industry (and powerful TV advertising) offers different magnesium- and zinc-containing products. However, one should be aware that organic forms of magnesium and zinc (such as citrate, aspartate, etc.) show a much higher bioavailability than inorganic forms (e.g., MgSO4 and ZnSO4). Neurometabolic therapy (provided in the medical centre Primavera MEDICA) is based on the combined use of magnesium and zinc in the form of asparaginates.



Effective decrease of hyperactivation cannot be achieved without blocking the AMPA-receptors. As non-toxic blockers of these receptors are not available, neurometabolic therapy includes a derivative of α-ketoglutaric acid. Because of the suppressive effect on the neuron excitability, this substance is essential for treatment of twitches, stereotypic and compulsive movements in children, for example, autism, as well as for anti-epileptic therapy. D-serine can also be used to suppress AMPA-receptivity. It is noteworthy that as a competitive blocker of AMPA-receptors, this amino acid racemate simultaneously activates the glycine site of NMDA-receptors.


To increase the efficacy of inhibitory processes, substances are used that have binding sites at the inhibitory GABA-receptor, i.e., benzodiazepines, barbiturates, taurine, muscimol, and β-alanine. Benzodiazepines were discovered in the XX century through the attempts to find an anxiolytic substance which would be more safe and effective than alcohol (first one was launched in 1960, nowadays, about 30 drugs of this group known as tranquilizers are available, such as diazepam, clonazepam, etc). It turned out, however, that benzodiazepines block endozepine (natural benzodiazepine receptor ligand normally present in the brain) receptor involved in various activities of the brain and, hence, produce serious adverse effects. Barbiturates known as sedative-hypnotics (phenobarbital, etc.) also have serious well-known limitations.



To enhance the inhibitory effect of the GABA-receptor system, neurometabolic therapy includes taurine and β-alanine. These compounds also produce sedative, anti-anxiety, and anti-epileptic effects, but they do not cause drowsiness, memory problems, and other side effects.



β-alanine is the only naturally occurring β-amino acid, thus, it is not involved in protein synthesis. Beyond being a neurotransmitter, β-alanine is a



component of pantothenic acid (vitamin B5), which itself is a component of coenzyme A, and carnosine, a naturally occurring peptide. β-alanine increases carnosine production and protein synthesis within muscles to enhance muscular strength and, simultaneously, reduce fat mass. What is necessary to know is that in early childhood, a growing brain is very much different from that in later childhood and adult age.


Despite my solid experience in electrofunctional testing, I never cease to be amazed at the positive changes in bioelectric brain activity that occur 40-50 minutes after administration of neurometabolic drugs. 



Gavrilenko A.Ya., 

M.D., physician, specialist in functional diagnostics










The inhibitory GABA system is malfunctioning until about one year of age (not known precisely). Moreover, GABAergic pathway at this age is activatory. Therefore, infant brain activation occurs without any inhibitory mechanisms (apart from, perhaps, taurine and serotonin, if these substances are produced in sufficient quantities).


Exogenous taurine barely crosses the blood-brain barrier. In the brain, taurine is produced as an end product of the amino acid cysteine metabolism. Therefore, increase in taurine production can be achieved via exogenous intake of cysteine. Taurine has an anti-epileptic effect, blocks aggressive reactions, and modulates the motor activity. Taurine plays an important role in the control of cell volume and antioxidant effects. In particular, antioxidant activity of taurine is triggered by the overloaded antioxidant cellular systems. The importance of taurine in maintaining water content inside the cells is illustrated by its high levels in animals living in salt water (turtles, oysters). Osmotic regulation in marine organisms is largely based on intracellular taurine content corresponding to salt concentrations in the environment.



Regulation of vascular lumen and endothelial function using neurometabolic therapy. Altered production of nitric oxide (NO) is a major factor for endothelial dysfunction and vascular tone impairment, regardless of the underlying cause. Nitric oxide has numerous functions: it regulates vascular tone (prevents vascular spasm), serves as a neuromediator, and plays a role in immune protection. Nitric oxide, which is relevant for immune defence, is produced primarily in macrophages after their activation by inflammatory molecules (cytokines) and corticosteroids. However, if the neuroinflammatory response is prominent, NO is overproduced, which can lead to toxic effects. Nitric oxide is produced in arginine-citrulline cycle, during which arginine undergoes conversion to citrulline (Fig. 5).


In the context of neurometabolic therapy, concomitant administration of arginine and citrulline is used to enhance nitric oxide production. Arginine is extensively converted to essential metabolites, including polyamines (spermine, spermidine), creatine, agmatine, glutamate, and proline.


Figure 5. Nitric oxide (NO) synthesis in the arginine-citrulline cycle 





Nitric oxide is a molecule with a short half-life. NO is stored and transported from the site of synthesis in complexes with sulphur-containing amino acids (cysteine, N-acetylcysteine), as well as glutathione (a peptide consisting of three amino acids, including cysteine). Nitrosothiols are considered to be universal endothelial relaxants, since they release nitric oxide upon demand of the body. Serotonin, bradykinin, and purine substances increase the nitric oxide production, mostly in the endothelial layer, which promotes dilation of blood vessels.



Cysteine plays an important role in the regulation of blood pressure and vascular tone through inhibition of angiotensin-converting enzyme (ACE) activity. ACE increases blood pressure via two mechanisms. First, it promotes production of angiotensin and aldosterone. Second, it inactivates bradykinin, which lowers blood pressure.



Bioenergetics of nerve cells. Neuroprotection. Stress-mediated activation of immunometabolic processes is followed by drastically increased free radical production. This is the main cause for disruption of cellular respiration. Natural exogenous substances or their endogenous analogues provide optimal antioxidant protection and support energy status within the neurons.


Sulphur-containing amino acids (cysteine, cystine, N-acetylcysteine) are actively involved in the neuroprotective mechanisms through the antioxidant action, removal of excessive glutamate activators, and inhibition of potential-dependent calcium channels.







N-acetylcysteine has been shown to quickly increase intracellular levels of glutathione, the most powerful intracellular antioxidant. In an in vitro model of neuronal death, N-acetylcysteine produced more significant protective effects than α-tocopherol and ebselen.


Higher extracellular levels of cysteine and cystine lead to reduced content of glutamate activators in neurons via cis-glu-transporter activity.






Thiol-disulfide system plays an important part in the regulation of tissue redox balance. Sulphur-containing substances more effectively prevent and reverse oxidative stress and increase neuronal resistance to hypoxia than well-known nootropics of piracetam (a cyclic GABA derivative) group.







It is noteworthy that glutathione, a most powerful cellular antioxidant, contains cysteine. Glutathione plays an important although less known role in transfer of amino acids across cellular membranes, undoubtedly supporting in this way normal cell functioning. The central role in this process belongs to oxoproline. Lack of this amino acid interfered with glutathione molecule assembly and, in general, reduced intracellular antioxidant defence.







Lower intracellular levels of reduced glutathione is closely related to malfunctioning mitochondria known as the powerhouse of the cell and, thus, leading to energy deficiency (ATP). However, even intravenous administration of reduced glutathione is of little if no use, because it is rapidly oxidized with a half-life of only 1.6 min. The solution of the problem was found in the synthesis of S-acetyl glutathione, which contains a protected SH-group (protection against oxidation is achieved via acetylation, same as in the acetylsalicylic acid). S-acetyl glutathione crosses cellular membranes without any oxidative losses and undergoes conversion into glutathione.







Antioxidant properties are also demonstrated by histidine, another amino acid. Together with copper and zinc, histidine simulate the active centre of Cu, Zn-superoxide dismutase and intercept superoxide (O2-) radical from a cascade of oxidative reactions. Antioxidant effect of carnosine (β-alanyl-histidine) is also delivered by the histidine residue within the molecule.


Regulation of cell energy supply is based on metabolism of purine compounds (Fig. 6).






Figure 6. Breakdown of purine nucleotides


Purine molecules participate in cell functioning in the following way. For proper functioning, sufficient energy (as adenosine triphosphate [ATP] molecules) should be stored in the cell. ATP activates neurons via specific receptors. As the cell performs its functions, ATP degrades to AMP and adenosine to ensure energy supply. Increase in AMP and adenosine levels (and simultaneous decrease in ATP levels) indicate energy deficiency and the need to re-synthesise ATP. Increased levels of AMP and adenosine slow down cell activities via their inhibitory receptors until energy-rich ATP molecules are synthesized de novo, and then ATP again stimulate specific receptors to activate cellular functions. Intermittent activation or suppression of purine receptors activates or slows down brain cell activity in accordance with energy supply and demand. For example, coffee contains caffeine, an antagonist of inhibitory purine receptors. Through blocking inhibitory receptors, caffeine causes persisting cellular activity and prevents the cells from slowing down and accumulating energy. Subsequently, caffeine causes rapid depletion of nerve cells and prevents their normal functioning.





To reduce neuron excitability and prolong time for energy accumulation, exogenous hypoxanthine can be used (Fig. 6) to slow down, by negative feedback mechanism, inosine breakdown and thereby increase adenosine and inosine content. As a result, sedative and anticonvulsive effects are achieved, blood pressure is decreased, and heart rate recovered. This therapeutic strategy activates the so-called rescue pathway, i.e., backup synthesis of macroergs from adenine. This pathway is essential to compensate for energy deficiency in the brain.





Under the conditions of high psychological or physical strain and overload, hypoxia, or injury, elevated adenosine levels are followed by increased production of hypoxanthine. Hypoxanthine is oxidised into xanthine and then to uric acid (Figure 6, reactions 4 and 5) by xanthine oxidase with the formation of multiple radicals. Serum xanthine oxidase levels are increased manifold under load, ischaemia, or hypoxia, and it becomes an additional source of toxic active oxygen radicals, which cause damage and death of nerve cells. Therefore, blocking xanthine oxidase (e.g., by allopurinol) may be protective in these situations.






Amino acids are mainly metabolised in the liver. Exceptions are the amino acids with branched carbon chain, i.e., valine, leucine, and isoleucine. In the body, they function as fuel and, which is most importantly, are oxidised in the brain and muscles.


To reduce neuroinflammation, it is reasonable to use 5-aminophthalhydrazide. It demonstrates strong anti-inflammatory effects through inhibited production of proinflammatory cytokines. It also exerts anti-epileptic action.





Vitamins. All vitamins are useful. They support hundreds of kinds of reactions. Often we prescribe B vitamins in combination with folic acid. Without going into too much detail about the role of vitamins, let us take vitamin B6 as an example. It is sometimes called the king of amino acid metabolism, because it is involved in reactions catalysed by almost all classes of enzymes.






It is impossible not to mention vitamin D. This vitamin acts on cell similarly to thyroid, adrenal, and sex hormones. Vitamin D receptors are found in the cell nuclei, and they regulate functions of genetic machinery.







Vitamin D deficiency is found in almost all patients with anxiety-depressive disorders, chronic stress, multiple sclerosis, and other diseases, as well as during pregnancy. Moreover, in our climatic conditions with no sufficient sunlight from October to April, vitamin D is guaranteed for the entire nation.







Neurometabolic substances for activation of cellular neuronal activity. In 1971, piracetam (Nootropil) was synthesized, giving rise to the whole class of drugs called nootropics. Paradoxically, no precise information about its mechanism of action is yet available. Pharmacological properties of these drugs have been studied much less extensively than their clinical effects. Nevertheless, there is an ongoing search for more effective drugs with fewer side effects. In this view, we believe it is appropriate to present a range of neurometabolic substances meeting, in our opinion, these requirements.







Nootropics are generally viewed as substances activating neural excitability, i.e., cognitive enhancers. As such, they influence the processes of concentration, consolidation, and recall of information, learning, and personal motivation.


Activation amino acids (L-isomers of glutamic and aspartic acids), as well as glycine, a co-activator, practically do not cross the blood-brain barrier. Chiral isomers of these amino acids, in particular their racemised D-isomers, may support neurotransmission and neuronal activity. D-amino acids do not undergo liver metabolism after oral administration and can directly cross the blood-brain barrier. They can facilitate correction of weakened interactions between the neurons and promote intracellular signal pathways of metabolic and genomic regulation. Of particular importance are D-glutamate, D-aspartate, and D-serine. Glycine does not have a racemate form. D-serine is an analogue of glycine in the brain, only with even better efficacy. Given that D-glutamate, D-aspartate, and D-serine have a selective action on stimulatory receptors, their critical role in brain maturation, development, and subsequent performance is obvious. It is noteworthy that levels of D-aspartate, D-glutamate, and D-serine in the foetal brain are very high. After birth, the levels of D-aspartate and D-glutamate decline, while D-serine remains consistently high. In adolescents and adults, its levels are half of those in the foetus.




A consensus view of the authors investigating cerebral turnover of D-amino acids is that variation in their levels are associated with decreased function of activation receptors.





Therefore, D-amino acid deficiency is a factor mediating inhibition of physiological processes, including brain development in children, and involved in the pathogenesis of neuropsychiatric disease.


An activating modality of neurometabolic therapy containing D-amino acids is administered in various clinical situations both in children and adults. For example, D-amino acids can be useful when it is necessary to improve nerve impulse conduction and to increase neuronal activity in demyelinating diseases (multiple sclerosis). Activating therapeutic regimens should be considered for the treatment of conditions characterized by disordered cognitive processes and memory, learning, or analysis skills, and when it is necessary to strengthen neurotransmission through the

combined effort of the inhibitory and excitatory neurons, i.e., in children with delayed or defective psychological development and speech, in elderly people with cognitive decline, or in otherwise (e.g., as a result of drug abuse) cognitively impaired individuals. Improved brain performance in the presence of D-amino acids may also occur by change in the efficacy of synapses, i.e., unmasking of dormant synapses (contacts between neurons).


In apoptosis, activation of neuronal intracellular processes is required to induce apoptosis and eliminate functionally defective nerve cells. Furthermore, D-serine has become the drug of choice for educational therapy in children with autism spectrum disorder and stereotypical obsessive movements. In this context, the use of D-serine is warranted by its potential to activate glycine binding sites on the NMDA-receptor and simultaneously inhibit the AMDA-receptor.

There is still another way to activate the nerve cells. Although the L-form of activation-promoting glutamic acid does not cross the blood-brain barrier, oral administration of glutamine results in its unrestricted delivery into the brain, where it is converted into glutamic amino acid (Figure 7).






Figure 7.(A) Synthesis of glutamic amino acid from glutamine in the nerve cells with activator functions; (B) synthesis of gamma-aminobutyric acid from glutamic acid in the nerve cells with inhibitory functions. 


Glutamine has an important ability to increase the efficiency of both the excitatory and inhibitory neuromediation. And this is not strange, since glutamine is the source for synthesis of activating glutamic amino acid (Figure 7A), which, in turn, is a source for synthesis of inhibitory gamma-aminobutyric acid (Figure 7B). This is exactly how it was conceived and designed by the nature: the most potent activator, glutamic acid, converts into the most potent inhibitor, gamma-aminobutyric acid, when the CO2 molecule cleaves away. This is the fundamental principle of maintaining excitatory-inhibitory balance in the brain.





In hyperactive children, improved attention and perseverance with lower level of impulsivity can be achieved primarily by the inhibitory modality of the neurometabolic therapy containing substances that increase the inhibitory and decrease the excitatory-inhibitory neuron balance (the effects of these drugs have been discussed above).


In children without hyperactivity, nootropic therapy can be started concomitantly with the so-called activating modality of the neurometabolic therapy. Short- and long-term potentiating effects can be obtained not only with the activation signal to the neurons.






We have shown that substances increasing membrane charge (β-alanine) or  

preventing activation (magnesium salts of aspartate and glycine) not only improve the


inhibitory neurotransmission, but also (indirectly) participate in the formation of long-term potentiation. The greater the membrane potential in neurons, the better is the filtering of weak indiscriminate activation signals. However, if a sufficiently strong, targeted activation signal is applied, cell response becomes more efficient. This is understandable, since the drugs that improve the course of inhibitory processes, especially those that are latent, are prerequisites for higher efficacy of excitatory processes.



Neurometabolic therapy normalizes brain performance and creates the basis for effective training sessions and, in particular, programmes for speech development.


Ryabinina I.V.,

physician, speech therapist 



Theoretically, substrate drugs (hypoxanthine, inosine- and thiol-containing compounds) are essential for long-term neuron activation, because appropriate response can be obtained only from the cells with sufficient energy status can demonstrate appropriate response.


Intracellular calcium is an important regulator of cellular fate: at normal levels, it is involved in signal transduction and amplification cascades and diverse physiological cellular responses. Elevated calcium concentrations trigger apoptosis (cell suicide). Low intracellular calcium levels adversely affect cell performance, including apoptotic events (it is typical for cancer cells).





We determined the number of calcium-active cells and the density of receptors in the calcium signalling pathway, i.e., regulating the injection of calcium ions from intracellular stores into the cytoplasm, in children with ADHD, autism, speech and developmental delay, hereditary syndromes (Downs, Angelman, Miller-Dieker). It was found that these parameters were reduced, just as in adults with demyelinising (multiple sclerosis) and degenerative (Parkinsons disease) diseases. Later, the effects of squalene derivatives (Sevit-Forte, Russian patent No. 2245143 issued in 2002) on these parameters have been studied. Detailed analysis of the results is presented in the monograph Neurochemistry of smile.Biological foundations of clinical neuroscience. 


It is noteworthy that universal normalizing effects of Sevit-Forte are seen in all types of receptors, both superficial and intracellular. We say universal, because it is effective in all cases of deviation from the norm. Normalising means that Sevit-Forte down-regulates the receptor synthesis if it is overproduced and up-regulates if it is deficient. If both receptors, superficial and intercellular, are expressed adequately, Sevit-Forte has no effect on their synthesis. The increased percentage of calcium-active cells following administration of this drug means that the pool of functionally competent cells is growing, and this favourable trend is observed in the blood, in the immune tissues, and in the nervous system.






Treatment strategy: multimodality, dosage, duration




When prescribing complex treatment regimens, it is important to explain how and when to take medications.


Mikhailova T.Yu., pharmacist


In view of all the above information regarding the diversity, interrelationships, and mutual dependency of multiple mechanisms of pathogenesis of any disease or condition, it is absolutely needed to apply combination therapeutic regimens containing several therapeutics targeted at the major pathophysiological elements. These regimens cannot be invariable throughout the treatment period and should be modified depending on the current treatment task. One medicine cannot cure a disease; it can only affect an individual symptom. 

Xenobiotics are natural substances, they do not accumulate in the body, become rapidly included into metabolic reactions (within 10-30 minutes), metabolised, and, after 3-4-hours, excreted from the body in the form of end products. Therefore, these drugs are recommended to take no less than 4 times a day.








The exact composition and dosage of drug products are usually revised during treatment period based on the clinical situation and specific condition. 



For example, in children with ADHD or developmental delay who demonstrate cognitive restriction, hyperactivity, lack of control, and anxiety, treatment is started with those products that inhibit neural excitability, increase energy potential, have anti-inflammatory and anti-anxiety potential, and affect endothelial function. After some period, the severity of symptoms decrease, attention and perseverance improve, and, hence, family and social communication also improve, the treatment scheme is supplemented with drugs activating neurotransmission and affecting neurogenesis.








Clinical improvement as the result of rescue therapy represents the first stage of recovery. The duration of the first phase of treatment is at least 4 to 12 weeks, and the outcome of this phase is remission.








Restoration of neurogenesis, which is always impaired under chronic stress, is an important determinant of treatment duration at the first phase and during the subsequent maintenance therapy. The recovery of neurogenesis will take time for the production, migration, and maturation of the neurons. In rodents, this period takes at least 30 days, and over 70 days in large animals (for example, macaques). 



This is why the maintenance therapy is needed. Extended maintenance therapy has different tasks in different diseases. For example, in children with developmental delay, learning problems, and, at the same time, to autism spectrum disorders, maintenance therapy is designed to help a primary treatment succeed and, at the same time, to support the development and maturation of the nervous system, including neurogenesis.


In anxious depression, cessation of primary treatment is associated with a high risk of relapse. Studies show that up to 75% of patients with anxiety-depressive disorders show relapse within 10 months of observation. Thus, the maintenance therapy can be essentially called anti-relapse.





The analysis of 31 randomised trials (4,410 patients) showed that maintenance therapy reduced the risk of relapse by approximately 50%. The same is true for demyelinating and neurodegenerative diseases.







The duration of the second phase is highly variable and depends on the severity of the disease, its duration, age, individual reactivity, and many other factors.







It is important to understand that treatment regimens of neurometabolic therapy affect not only the neuroglia component of the central nervous system, but also the immunocompetent blood cells and other immunocompetent tissues. All these tissues  


have similar receptor machinery and, similarly to the cells within the central nervous system, synthesise cytokines, biogenic amines, neurotrophins, neuropeptides, and hormones. Therefore, it is more appropriate to refer neurometabolic therapy as neuroimmunometabolic therapy.Certainly, the Medical Centre PRIMAVERA MEDICA named after A.P. Khokhlov also provides conventional medical care. These recommendations, however, can be obtained from any other medical institution, while at Primavera MEDICA, patients receive much more, including neurometabolic therapy significantly improving patients outcomes. 



We get calls regarding a variety of issues. It is necessary to look into each situation, so that the patient could obtain complete information and proper appointments for convenient time. We are trying to be as friendly and accommodating as possible.


Tsvetkova E.V., receptionist 



Medical Centre


We always welcome our patients friendly and, at the same time,
professionally support our physicians.


Safronova O.E. and Galushko N.E.,



PRIMAVERA MEDICA Medical Centre named after A.P. Khokhlov was founded in 1993. A distinctive feature of our centre is that maximum therapeutic efficacy is achieved using the combination of neuroimmunometabolic therapy and traditional medicines. Regimens of neuroimmunometabolic therapy are the result of many years of serious scientific and experimental studies. It is not correct to assume that this therapy is designed only for nervous system diseases and immune disorders (as follows from its name). This therapy is used in multiple medical fields: neurology, psychiatry, immunology, ophthalmology, and gynaecology, as well as for internal and surgical diseases. Therefore, physicians of various specialties are working in the PRIMAVERA MEDICA Medical Centre named after A.P. Khokhlov.





In recent years, it has become clear that for successful treatment of menstrual cycle disorders, infertility, hormonal imbalance, and other conditions neurometabolic therapy should be combined with other treatment modalities. In particular, Sevit-Forte must be taken to treat endometriosis, adenomyosis, and uterine fibroids. 



Ostapishina I.M.,M.D., gynaecologist





The eye is part of the brain located at a small distance. Everything acting on the brain also acts on the organ of vision, especially the retina and the visual area of the brain. Therefore, we use neurometabolic therapy for many forms of visual impairment.


Yudina Yu.V., M.D.,PhD, ophthalmologist
































Pathogenesis and not rarely the causes of many somatic diseases are closely related to impaired nervous regulation and immune disorders. We achieve better results when such diseases are treated with the combination of conventional and neuroimmunometabolic therapy. Such diseases include psoriasis, eczema, ulcerative colitis, haemorrhoids, anal fissure, obliterating endarteritis, trophic ulcers, gastric ulcer and duodenal ulcer and many others, including benign tumours (uterine fibroids, benign prostatic hyperplasia). 



Panova V.G.,M.D.,surgeon 


EEG monitoring







With time, we found how unique is the human brain, even in a healthy human being, needless to say about the affected one.


In fact, only electrophysiological methods, i.e., electroencephalography (EEG), are currently used to study brain performance.






Indeed, EEG is a sensitive technique, and its readings change during the day depending on many factors (asleep or awake, tiredness, tension, any activity). EEG also changes after administration of a drug. It is important to understand that EEG will change in a different way after taking the same drugs in patients with same diagnosis and clinical manifestations of the disease.



Baseline EEG



EEG recorded 1.5 hours after administration of Aminovil-R






EEG monitoring is a necessary diagnostic test. We carry it out at the first visit to evaluate the bioelectric activity of the brain, then for testing the drugs, and to assess changes in brain activity during and after therapy. 


Alekseeva M.V.,M.D., physician, specialist in functional diagnostics 



Therefore, in particularly complex cases, we act as follows: baseline EEG is conducted, then a patient takes a drug, and EEG is recorded again after 1-1.5 hours.


Comparative analysis of paired EEG (using histograms, spectral analysis, and mapping) provides detailed information on the neurofunctional mechanisms of brain damage and gives a meaningful estimate of chances for pharmaceutical correction of the defects found. Based on this information, an appropriate treatment regimen can be chosen to achieve the desired therapeutic effect. In other words, through EEG monitoring, we can see how favourably the prescribed substance is accepted by the brain, or, figuratively speaking, whether it likes it or not. 


All of the above (EEG-based choice and modification of therapeutic regimens) is particularly relevant for epilepsy management. Moreover, we believe that prescription of any drug (both neurometabolics and traditional anticonvulsants) for this disease is best carried out after EEG.


During treatment period, the clinical condition of the patient improves (both motor and cognitive functions). It is evident that clinical improvement reflects normalization of neurotransmission and bioelectric activity in the brain. Therefore, it is clear that during further therapy, EEG is recorded again, when the regimen is to be changed.













Neurometabolic drugs used in the Medical Centre






NEUROMETABOLIC DRUGS belong to the group of food supplements (biologically active food supplements). They were designed and tested in accordance with the legislation of the Russian Federation and listed in the Federal Registry of Biologically Active Food Supplements of the Russian Ministry of Healthcare. PRIMAVERA MEDICA Medical Centre produces 23 proprietary neurometabolic drugs. Each of these products can act individually, but they complement each other if used in combination. Therefore, we usually prescribe treatment regimens containing several drugs.


Production of neurometabolic drugs, same as pharmaceuticals in general, is a responsible task.One needs to be accurate to a milligram, precise, and sterile.


Pokrovskaya O.N., manufacturing specialist





We can confidently assert that these drugs have no side effects and do not cause complications, especially because they have natural and physiological structure.



Scientific work



Research and development of METABOLIC PRODUCTS and studies of treatment modalities were conducted under joint effort of the Primavera MEDICA Medical Centre and the leading specialised institutions.



In accordance with the agreement on joint activity between the Primavera MEDICA and the Moscow City Department of Healthcare, we studied the efficacy of NEUROMETABOLIC THERAPY in neonates with varying degrees of prematurity and severe signs of perinatal lesions of the central nervous system. NEUROMETABOLIC THERAPY was shown to normalize reflexes and other neurological symptoms in newborns, including consolidation of the sucking reflex, which is especially important for premature babies. In addition, there was a reduction in the symptoms of intracranial hypertension syndrome and advanced neuro-reflex irritability. Subsequent observation showed that children who received


  • All the achievements of PRIMAVERA MEDICA are the result of extensive scientific research. The successful work of our physicians is based on a combination of scientific research and continuous monitoring of global medicine advances. 

Sokolova S.A. , research fellow



NEUROMETABOLIC THERAPY developed better during the first year of life. This work resulted in the newsletter of the Moscow City Department of Healthcare entitled Experience with neurometabolic therapy for combined treatment of perinatal lesions of the central nervous system to heads of paediatric hospitals, neonatologists, and paediatricians.



In 2001, the executive committee of the Association of Russian Paediatricians recommended to use guidelines METABOLIC THERAPY IN PAEDIATRICS as a manual.



In 2003, the Moscow City Department of Healthcare approved Methodical guidelines for the use of METABOLIC THERAPY drugs for the treatment of perinatal lesions of the central nervous system and infantile cerebral palsy.



In 2004, the Moscow City Department of Healthcare issued an information letter to Heads of hospitals regarding the use of Biologically Active Supplements Aminovit for treatment of alcohol abuse.



In 2004, a series of clinical trials were completed in the clinics of the Moscow City Department of Healthcare. Based on the results of these trials, reports on the clinical efficacy of NEUROMETABOLIC THERAPY for treatment of development and speech delays, autism, stuttering, and drug addiction were prepared.


The network structure of metabolic therapy



NEUROMETABOLIC THERAPY has become widely used. To improve accessibility of neurometabolic therapy to patients, PRIMAVERA MEDICA established partnerships with medical institutions in Russia and in other countries (for addresses and telephones, please contact PRIMAVERA MEDICA Medical Centre).




Rehabilitation centre New medical technologies


Czech Republic , Prague , Na Vaclavce, 44





(004202 5) 156 23 22, 156 33 20











Republic of Bulgaria , Plovdiv ,


Alexandra Stamboliyskogo avenue
, 105.


(0035932) 650 872, 650 871









Republic of Serbia , Beograd , Bistrkhka, str. 22.


(00381 11) 329 34 41, 329 34 42


Regional Paediatric Hospital


Blagoveshchensk, 675000, Oktyabrskaya street, 108.


(416-2) 444 873


OOO Manus


Vladivostok, 690091, 1aya Morskaya street, 4.


(4232) 414 141, mob. 906 464, fax 411 465


OOO Medical Centre Neuron


Vladivostok, 690091, Ostryakova avenue, 27.


(4232) 251 462 (reception), fax 267 426


OOO Neuromed


Volgograd, 400138, Zemlyachki street, 74.


(8442) 398 692, fax 347 389


OOO Bezlekarstvennaya meditsina


Krasnoyarsk, 660022, Gorkogo street, 20.


(3912) 276 700, fax 218 311


OOO Salus


Novosibirsk, Kropotkina street, 98/2,


Gagarinskaya subway station,


(383) 226 55 86, fax 348 31 40


Regional paediatric clinical hospital


Omsk, 644001, Kuibysheva street, 77.


(3812) 361 640, telephone/fax 362 220


LDK Zdorovye


Rostov-na-Donu, 344082, Ostrovskogo pereulok, 42.


(863) 240 69 70, fax 243 46 52


Public association Vozrozhdeniye



Samara, 443099,
Kuibysheva street
, 113.


(846) 333 21 14, 333 24 56


Pharmacy # 406 OOO Mechta A


Stavropol, 355029, Lenina street, 406.


(8652) telephone/fax 351 721


OOO Tsentr manualnoi meditsini


Khabarovsk, 680000, Amurski boulevard. 17.


(421-2) telephone/fax 309 309




How is treatment carried out?



NEUROMETABOLIC THERAPY is administered in an outpatient setting. This means that patients periodically (every 5-7 days) visit a doctor for examination and tailoring of therapy, because changes in their condition on neurometabolic therapy occur rapidly. For certain diseases, one course of treatment is sufficient. Such diseases as cerebral palsy or delay in psychological and speech development usually require 3 to 4 courses of therapy and, in severe cases, up to 5-7 courses of treatment. Maintenance therapy is required between the courses of treatment.



Consultations are provided by highly qualified physicians, gynaecologists, geneticists, neurologists, oncologists, ophthalmologists, surgeons, psychoneurologists, and others.



During treatment, all necessary tests required for diagnosis and objective control of response to therapy are conducted. PRIMAVERA MEDICA Medical Centre named after A.P. Khokhlov is equipped with modern ultrasound, ophthalmological, and gynaecological equipment. We carry out psychophysiological investigations, electroencephalography, and brain echoencephalography, and almost all laboratory tests.





In our rehabilitation department, all modern equipment and techniques are available for training patients after neurometabolic therapy.












Neurometabolic therapy reduces weight, increases strength, and improves muscle coordination. Therefore, the patient must simultaneously perform special rehabilitation exercises so that that they learn to use their potential as appropriate to their age. 

Efremova L.N., M.D.,physician, physiotherapist   








1993 A product for treatment of brain diseases.


1993. No. 2014082 A method for detection of cancer diseases.


2001. No. WO 02/092066 A1 An anti-tumour drug and method for its production.


2001. No. 2182480 An anti-tumour drug and method for its production.


2001 No. 2197957 A drug and method for elimination of side effects of anti-tumour agents.


2002. No. 2245143 Amino acid preparation with anti-tumour effect, and method for its production.


2002. No. 2238723 Analgesic and anti-contracture drug for external use.


2003. No. 2252756 A drug against alcoholism and drug addiction, and method for its production.



Articles and presentations



Biochemical basis of Primavera metabolic therapy. (European scientific journal OM & Ernahrung Zurich-Stuttgart-Salzburg, 2006, No. 115) Dotsenko A.N., PhD.


Metabolic therapy for treatment of brain diseases.(Presentation at the 50th Annual Congress of the human brain. Windmoor , Pennsylvania , United States , 4-6 May 2005 .)Dotsenko A.N., PhD


Metabolic therapy for treatment of brain diseases.(Presentation at the Symposium of Orthomolecular medicine. Prague , Czech Republic , 25-27 February, 2005) Blinnikova O.E., PhD, Associate Professor, physician, geneticist; Dotsenko A.N., PhD.


Effects of amino acid compounds on electrophysiological parameters and functional activity of neurons. Neurophysiological analysis.(Presentation at the Symposium of Orthomolecular medicine. Prague , Czech Republic , 25-27 February, 2005)Kudryashov I.E., PhD; Dotsenko A.N., PhD.


Role of metabolic therapy in the treatment of adult epilepsy.(European scientific journal OM & Ernahrung. Zurich-Stuttgart-Salzburg, 2005, No. 110) Roschina N.A., PhD, Associate Professor, physician, neurologist; Dotsenko A.N., PhD.


Therapeutic efficacy of dietary supplements for treatment of dependencies.(European scientific journal OM & Ernahrung. Zurich-Stuttgart-Salzburg


2004, No. 109) Dotsenko A.N., PhD; Khokhlov, A.P., PhD, Professor; Shamov S.A. , PhD, Associate Professor; Markin E.E.


New concept of pathogenesis and treatment of lateral amyotrophic sclerosis (LAS).


(European scientific journal OM & Ernahrung. Zurich-Stuttgart-Salzburg, 2004, No. 108) Khokhlov A.P., PhD, Professor; Dotsenko A.N., PhD; Roschina N.A., PhD, Associate Professor, physician, neurologist.


Metabolic therapy for management of perinatal lesions of the nervous system and cerebral palsy. (European scientific journal OM & Ernahrung. Zurich-Stuttgart-Salzburg, 2004, No. 107) Khokhlov A.P., PhD, Professor; Semenova K.A., PhD, Professor, Emeritus Scientist of the RSFSR; Dotsenko A.N., PhD.


Effects of new squalene derivative Sevit-F upon human tumours in nude mice.


(Theoretical, scientific and practical journal Russian Biotherapeutic Journal. Moscow, 2004, No. 2, Vol. 3) Khokhlov A.P., PhD, Professor; Treshchalina E. M., PhD; Dotsenko A.N., PhD; Sedakova L.A.; Andronov N.V., PhD; Gerasimova G.K., PhD, Professor.


The use of biologically active supplement Aminovit for treatment of patients with alcohol abuse.Newsletter of the Moscow Department of Healthcare, 2004.


Correction of psychoneurological development and phenotype in patients with Down syndrome receiving metabolic therapy.(European scientific journal OM & Ernahrung. Zurich-Stuttgart-Salzburg, 2003, No. 106) Khokhlov A.P., PhD, Professor; Blinnikova O.E., PhD, physician, geneticist.


Prospects of using amino acids in neurology and oncology.(European scientific journal OM & Ernahrung. Zurich-Stuttgart-Salzburg, 2003, No. 105) Khokhlov A.P., PhD, Professor; Dotsenko A.N., PhD.


Metabolic therapy for management of perinatal lesions of the nervous system and cerebral palsy.


(Report on the Scientific and Practical Conference of Russian Paediatricians, Moscow , Russia , 23-24 September 2003; Scientific and Practical Journal of the Russian Paediatricians Union Pharmakopia in Paediatrics. Moscow , 2003, Vol. 2, Appendix 2) Khokhlov A.P., PhD, Professor; Semenova K.A., PhD, Professor, Emeritus Scientist of the RSFSR; Dotsenko A.N., PhD.


Cytotoxic effects of Sevit-Fand aged amino acids in the N-9 human lymphocytic leukaemia cell culture. (Theoretical, scientific and practical journal Russian Biotherapetic Journal. Moscow, 2003, No. 1, Vol. 2) Khokhlov A.P., PhD, Professor; Dotsenko A.N., PhD; Osipova E.Yu., PhD.; Astrelina T.A., PhD; Belokhvostova A.S., PhD.


Results of screening of a new squalene derivative for antitumor activity.


(Theoretical, scientific and practical journal Russian Biotherapeutic Journal.


Moscow, 2003, No. 1, Vol. 2) Khokhlov A.P., PhD, Professor; Dotsenko A.N., PhD; Treshalina E.M., PhD; Sedakova L.A.; Andronov N.V., PhD; Gerasimova G.K., PhD, Professor.


Molecular basis of the mechanism of chronic stress formation.(European scientific journal OM & Ernahrung. Zurich-Stuttgart-Salzburg, 2003, No. 104) Khokhlov A.P., PhD, Professor; Dotsenko A.N., PhD.


Guidelines for the use of metabolic therapy drugs for treatment of perinatal central nervous system lesions and cerebral palsy.


Guidelines of the Moscow Department of Healthcare, 2003.


The use of amino acid compounds in paediatric psychotherapy.


(Proceedings of the Anniversary Scientific and Practical Conference marking the 10th anniversary of the Division of Medical Psychology of Samara State Medical University Clinical psychology and practical healthcare. Samara, 12-13 September 2002)Konnov S.V.


Cytotoxic effects of Sevit-F in the N-9 human lymphocytic leukaemia cell culture. (Theoretical, scientific and practical journal Russian Biotherapetic Journal. Moscow, 2002, No. 2, Vol. 1) Khokhlov A.P., PhD, Professor; Dotsenko A.N., PhD; Belokhvostov A.S., PhD; Osipova E.Yu., PhD.; Astrelina T.A., PhD; Vdovichenko K.K., PhD; Sidorova I.K.


Clinical manifestations, classification and diagnosis of Ehlers-Danlos syndrome in light of modern molecular genetic studies. (New surgical archive. Moscow, 2002, No. 4, Vol. 1) Khokhlov A.P., PhD, Professor; Dotsenko A.N., PhD; Belokhvostov A.S., PhD; Osipova E.Yu., PhD.; Astrelina T.A., PhD; Vdovichenko K.K., PhD; Sidorova I.K.


Role of metabolic therapy in the treatment of genetic disorders.(Presentation at the 4th Balkan Congress of geneticists. Novi Sad , Yugoslavia , 24-26 August 2000; International Journal of medical genetics BJMG. Sofia, 2000, No. 2) Khokhlov A.P., PhD, Professor.


Evaluation of efficacy of amino acid composite Provit for early comprehensive medical rehabilitation of children with perinatal injuries of the central nervous system. (Russian Gazette of Perinatology and Paediatrics. Moscow, 2000, No. 2) Degtyarev D. N., d. m., Professor, Chief Neonatologist (Moscow); Khachatryan A.V.; Navasardyants D.G., PhD; Kyshtymov M.V; Volodin N. N., PhD, Professor, Academician of the Russian Academy of Medical Sciences.


Games and exercises for development of hand motor skills.(Practical manual. Moscow , 1999) Khokhlov A.P., PhD, Professor; Dotsenko A.N., PhD; Ryabinina I.V.


Testing of amino acid composite Provit in preterm infants with perinatal encephalopathy.Newsletter of the Scientific and Research Centre for Paediatrics of the Russian Academy of Medical Sciences, 1998.


Changing of the content of neurospecific proteins, neurospecific enolase, leucine-aminopeptidase and cytokine tumor necrosis factor in children with perinatal injuries of the central nervous system. (Paediatriya, Moscow , 1998, No. 5) Volodin N. N., PhD, Professor, Academician of the Russian Academy of Medical Sciences; Degtyarev D. N., PhD, Professor, Chief neonatologist (Moscow); Khachatryan A.V.; Khokhlov A.P., PhD, Professor; Navasardyants D.G., PhD.


Role of metabolic disorders in the pathogenesis of perinatal encephalopathy and cerebral palsy and optimisation of potential treatment for these diseases. (Gazette of Practical Neurology, Moscow , 1998, No. 4) Semenova K. A., PhD, Professor, Emeritus science worker of the RSFSR; Sinitsyn G.P.; Najchuk S.N.; Khokhlov A.P., PhD, Professor.


Efficacy of the drug Provit for therapy of perinatal CNS lesions in infants.(Presentatio at the 2nd Congress of the Russian Association of Perinatal Medicine. Moscow, 25-26 September 1997)Dmitrieva N.V., PhD, Professor; Tkachenko T.G., PhD, Assistant Professor; Dmitriev A.V., PhD, Professor; Nesterova E.I.; Filimonova I.G.


Mobility exercises on round therapeutic balls for children and adults with cerebral pathology.(Practical manual. Moscow , 1996) Khokhlov A.P., PhD, Professor; Dotsenko A.N., PhD.


A new method to reduce stress levels in children with disabilities.(Presentation at the 2nd Russian Scientific and Practical Conference Anthropogenic impact and human health, Kaluga, Russia, 25-27 April 1995)Khokhlov A.P., PhD; Dotsenko A.N., PhD.


Physiology of muscle tone and voluntary movements.


(Practical manual. Moscow , 1994) Andrianov V.V., PhD; Dotsenko A.N., PhD.



Evidence-based medicine


Clinical trials of neurometabolic drugs



Clinical trials of metabolic therapy drugs for treatment of psychological and speech development delay, autism, and stuttering.State Research Centre of Social and Forensic Psychiatry named after V.P. Serbski. Children's Psychiatric Hospital No. 6, Moscow . 2004.


Open controlled clinical trial of BAS Aminovit for treatment of patients with alcohol abuse.Moscow State Medical Dentistry University , Department of Psychiatry, Narcology and Psychotherapy. Narcological Clinical Hospital No. 17, Moscow . 2004.


Open controlled clinical trial of BASs Aminovit and Cerebron-R for cessation of opium withdrawal syndrome.Moscow State Medical Dentistry University , Department of Psychiatry, Narcology and Psychotherapy. Narcological Clinical Hospital No. 17, Moscow .2004.


Clinical trials of Provit and Sevit for treatment of newborn infants (preterm and term) with perinatal asphyxia and ischaemic lesions of the Central Nervous System.Ministry of Healthcare of the Republic of Bulgaria , Neonatology Clinic of the University Hospital for active treatment of paediatric diseases, Sofia . 2003.


Efficacy of combination therapy with Sevit-F, Vitamixt-F and Immunol for oncohaematological diseases.Research Institute of Paediatric Haematology of the Russian Ministry of Health. City Paediatric Clinical Hospital named after S.P. Botkin. 2003.


The use of Sevit-K for treatment of severe dystrophic disorders of photoreceptive system of the eye.Municipal Central Children's Clinical Hospital, Orenburg . 2000.


Clinical trial of Sevit and Aminovil in the framework of the programme Treatment of sick children with exogenous intoxication.Russian Medical Academy of Postgraduate Education, Department of Paediatric toxicology. Childrens city clinical hospital No. 13 named after N.F. Filatov, Moscow . 1999.


Experimental study of the efficacy of the drug Sevit-K in the form of eye drops for treatment of mechanical and thermal injury of the cornea.State Institution Research Centre of eye diseases of the Russian Academy of Medical Sciences. 1999.


Clinical trial of the drug Sevit-K in the framework of the programme Treatment of patients with chronic gastritis, gastroduodenitis, and peptic or duodenal ulcer.


Russian State Medical University , Department of Paediatrics and Paediatric Infections. Children's Psychiatric Hospital No. 21, Moscow . 1999.


Clinical trial of the drugs Provit and Sevit in preterm infants with perinatal lesions of the central nervous system.Research Center of Children Health , Russian Academy of medical sciences, Department of Prematurity. 1998.


Testing of amino acid composite Provit in preterm infants with perinatal encephalopathy.Research Centre of Paediatrics, Department of Neonatology. 1998.


Clinical trial of biologically active food supplements in children sick due to toxicological factors.Russian Medical Academy of Postgraduate Education, Department of Paediatric toxicology. 


Childrens city clinical hospital No. 13 named after N.F. Filatov, Moscow , Childrens toxicological centre. 1998.


Results of a follow-up survey of the main and control groups during the first year of life.Russian State Medical University , Department of Neonatology. Childrens city clinical hospital No. 13 named after N.F. Filatov, Moscow . 1997.


Clinical trial of food supplement Vitamixt-R for treatment of viral hepatitis.Moscow Medical Dentistry Institute, Department of Infectious Diseases. Clinical Infectious Diseases Hospital No. 2, Moscow . 1997.


Clinical trials of dietary supplement Provit in newborns with perinatal lesions of the central nervous system.Russian State Medical University , Department of Neonatology. Childrens city clinical hospital No. 13 named after N.F. Filatov, Moscow . 1996.


Treatment of perinatal encephalopathy in newborns using Provit.


Regional Clinical and Diagnostic center for Children, Ryazan . 1996.


Results of the use of Provit.Children's outpatient clinic No. 100, Moscow . 1996. Testing of Provit. City Clinical Hospital, Vladivostok . 1996.


Treatment of perinatal encephalopathy in newborns using Provit.


Municipal Children's Diagnostic and Rehabilitation centre, Orenburg . 1996.




Collection of scientific papers


edited by Professor A.P. Khohlov, PhD


PRIMAVERA MEDICA Medical Center 1996.



Perinatal encephalopathy.Semenova K.A., PhD, Professor, Emeritus scientific worker of the RSFSR.


The efficacy of amino acid composits in adults with cerebral palsy.Savin A.A., PhD, Professor.


Metabolic therapy for impaired speech development.Ivanushkina I.Yu., physician, psychiatrist


Dynamics of EEG changes during metabolic therapy in children with mental retardation.Andreeva O.V., PhD, physician, specialist in functional diagnostics.


The use of amino acid composits for treatment of delayed mental development in patients with cerebral palsy.Parkanova S.A., physician, psychiatrist.


Treatment of patients with hereditary syndrome pathology using amino acid composits. Blinnikova O.E., PhD, Associate Professor, physician, geneticist, Demina N.A., Emeritus physician of the RSFSR, physician, geneticist.


Potential of metabolic therapy for the treatment of Downs syndrome.Khokhlov A.P., PhD, Professor; Blinnikova O.E., PhD, Associate Professor, physician, geneticist, Demina N.A., Emeritus physician of the RSFSR, physician, geneticist.


The use of amino acid composits for treatment of children with malformations of the central nervous system.Bezprozvanova T.N., PhD, Assistant Professor, physician, neurosurgeon.


The use of amino acid compounds for epilepsy treatment.Khokhlov Yu. K., PhD, Assistant Professor, physician, neurologist; Fomicheva G.N., physician, specialist in functional diagnostics.


Analysis of the effects of amino acid composits upon neuropsychological and psychopathological disorders associated with epilepsy and epileptiform syndromes.Korableva T.I., psychiatrist.


Multiple SclerosisHaydarov B.T., PhD, neurologist.


The prospect of using amino acid preparations to treat post-stroke motor dysfunction.Parfyonov V.A., PhD, Professor, neurologist.


Experience with amino acid composits in lateral amyotrophic sclerosis (LAS).Roshina N.A, PhD, Associate Professor, neurologist.


Treatment of parkinsonism with amino acid compounds.Gerasimova O.N., PhD, neurologist.


Experience with the use of metabolic products in narcology.Novikov S.P., narcologist.


Cerebral palsy and amaurosis. The potential to restore vision.Yudina Yu.V., PhD, ophthalmologist.


Metabolic therapy for treatment of age-related cataracts.Yudina Yu.V., PhD, ophthalmologist; Yudina E.A., ophthalmologist of the highest professional category; Khokhlov A.P., PhD, Professor.


Metabolic therapy for treatment of corneal diseases of the eye.Yudina Yu.V., PhD, ophthalmologist of the highest professional category.


Metabolic therapy of genital endometriosis.Ganchina N.I., gynaecologist-endocrinologist.


Experience with treatment of uterine fibroids using the drug Sevit-Forte.Agnaeva N.Z., PhD, gynaecologist.


Treatment of benign prostatic hyperplasia with natural metabolites.Khokhlov A.P., PhD, Professor; Shirshov O.N., PhD, surgeon; Dotsenko A.N., PhD.


The use of metabolic therapy products for treatment of skin ulcers of the lower limbs.Khokhlov A.P., PhD, Professor; Shirshov O.N., PhD, surgeon; Dotsenko A.N., PhD.


The use of natural metabolites for treatment of anorectal area diseases. Khokhlov A.P., PhD, Professor; Shirshov O.N., PhD, surgeon, et al.



For detailed information on presentations, manuscripts, and other scientific materials please visit the official website of the Primavera Medica Medical Center





We designed this brochure as an informational and promotional material. However, it turned out to look more like a scientific and educational monograph. We choose not to overload it with percentages and numbers describing the statistics of treatment efficacy or the growing number of patients coming to us.


Such conditions, as post-stroke and craniocerebral injury, a large group of hereditary diseases (primarily, Down's syndrome), endometriosis and uterine fibroids (gynaecology), substance abuse (alcohol, drugs, gambling), and many other internal and surgical diseases (gastric ulcers, venous stasis ulcers, nonspecific ulcerative colitis, benign


I worked for more than 15 years as a consulting representative of PRIMAVERA MEDICA in several European countries, where neurometabolic therapy is also sought after. During more than two decades, our Centre provided neurometabolic therapy to patients not only from Russia , but also from many other countries. 


Chmil V.G.,M.D.,neurologist 


tumours, e.g., benign prostatic hyperplasia, haemorrhoids, and anal fissure) are not discussed in this brochure in detail. This information, including results and reports of various clinical trials, can be found on This brochure describes our achievements, knowledge, views, and theories. In fact, some experimental data have the status of discoveries. The use of neurometabolic therapy and its efficacy in these diseases is well-developed, tactically robust, and tested by time.




Treating patients with hereditary diseases, we rely on activating and development-promoting properties of neuroimmunometabolic therapy, as well as its ability to modify behaviour if hyperactivity, aggression, or lack of motivation are present. This is relevant for many chromosomal and genetic diseases, primarily Down's syndrome. 


Demina N.A.,M.D., Emeritus physician of RF, geneticist. 















We provide self-questionnaires that allow each reader to assess the health status.



Anxiety and depression scale



Scientists believe that emotions play an important role in the pathogenesis of most diseases. If your physician learns more about your experiences, he/she will be able to help you better. This questionnaire is designed to help your physician understand how you feel. Ignore the numbers and letters on the left-hand side of the questionnaire. Read each statement carefully and mark with a cross the answer that most closely matches how you felt in the past week. Don't hesitate too long on each statement. Your first reaction will always be correct.



The scale consists of 14 statements, assessing 2 subscales:



Subscale A anxiety: odd statements - 1, 3, 5, 7, 9, 11, 13;


Subscale D depression: even statements - 2, 4, 6, 8, 10, 12, 14.








I feel the tension, I don't feel right






All the time












From time to time, sometimes






Not at all






What brought me great pleasure in the past now gives me the same sense






Definitely true






Probably true






True only to a small degree






Not true at all






I feel fear as if something terrible is about to happen






Definitely true, and the fear is very strong






True, but the fear is not very strong






Sometimes, but it does not bother me






Not at all






I can laugh and see fun in any event






All the time












From time to time, sometimes






Not at all






Troubled thoughts are going round and round in my head












Most of the time






From time to time, and not too often






Only sometimes






I am feeling cheerful






Not at all






Very rarely












Almost all the time






I can easily sit down and relax






Definitely true






Probably true






Only occasionally






Not at all






It seems to me that I started doing everything slowly






Almost all the time


















Absolutely not






I feel inner tension or shiver






Not at all


















Very common






I don't pay attention to my appearance






Definitely true






I don't pay to it as much time as needed






Maybe I've started paying less attention to it






I look after myself the same way as I did before






I feel restless, as if I constantly need to move






Definitely true






Probably true






True only to a certain extent






Not at all






I believe that my occupation (including hobbies) can bring me a sense of satisfaction






In the same way as usual






Yes, but not to the same extent as before






Much less than usual






Not at all






Sometimes I have a sudden sense of panic






Indeed, very often






Quite often






Not too often






Not at all






Can I get the pleasure from a good book, radio, or TV
























Very rarely


Now check if you answered all the questions




When interpreting data, please take into account the total value for each subscale. Three options are available, depending on the final value.


0-7 correspond to normal state;


8-10 is subclinical anxiety/depression;


11 and above correspond to clinical anxiety/depression.







Depression self-assessment questionnaire





0 - I don't have a bad temper


1 - I experience low mood or melancholy


2a - I am constantly experiencing depression or melancholy and cant get rid of them


2b - I am so unhappy, and my mood is so bad, that it gives me torment


3 - I'm so unhappy, and the mood is so bad, that I can't take it





I don't feel any particular pessimism or confusion about the future


I don't feel confusion about the future


2a - I feel that I have nothing ahead


2b - I feel like I will never be able to overcome the difficulties facing me


I feel that the future is hopeless, and that there is nothing I can fix anymore





I don't feel anything resembling incompetence


I believe that I have more setbacks than an average person


I feel that I have done too little of what is worthwhile or deserves attention


2b - looking back at my life, I can see only a series of failures


I feel that I totally failed as a person (father, mother, husband, wife)





I am quite satisfied with myself


I feel like I am missing something most of the time


I don't get the level of satisfaction I used to


I dont feel any satisfaction


Any event makes me feel unhappy



E - guilt


I don't feel guilty for anything


I feel like I am bad and unworthy for a significant part of the day


2a - I feel a sense of guilt


2b - I feel like I am bad and unworthy almost all the time


I am always feeling that I am a very bad and useless person





0 - I am not waiting for punishment from anywhere


1 - I feel that I can something happen


2 - I feel that I am being punished, or that will be punished


3a - I feel that deserve punishment


3b - I want to be punished





0 - I am not disappointed in myself


1A - I am disappointed in myself


1b - I do not like myself


2 - I am disgusted with myself


3 - I hate myself





0 - I do not think that I am worse than others in any way


1 - I take my weaknesses and errors too critically


2a - I blame myself for everything going wrong


2b - I know that I have many major flaws





0 - I dont even think about causing harm to myself


1 - I have suicidal thoughts, but I won't do that


2a - I would rather die


2b - I have a plan of how to commit suicide


2c - I feel that my family would be relieved if I died


3 - I would kill myself if could





0 - I cry no more than usual


1 - I now cry more than usual


2 - I'm crying all the time and I cant stop


3 - before, I could start crying, but now I cant anymore even when I want to





0 - I am more irritable now than usual


1 - I get irritated and cranky more than usual


2 - I am always feeling irritated


3 - things that would usually annoy me do not do so anymore





0 - I haven't lost interest in people


1 - I am now less interested in people


2 - I lost almost all interest in people and they do not cause any feelings in me


3 - I lost interest in people, and I don't care about their existence anymore





0 - I am as decisive as before


1 - I am not as confident as before, and try to postpone making decisions for later.


2 - I hesitate to do anything without assistance


3 - I can no longer make decisions at all





0 - I look worse than before


1 - I am concerned that I look older and unattractive


2 - I notice stable changes in my looks that make me unattractive


3 - I feel that my appearance has become more ugly and repulsive






0 - I can work just as well as before


1a - I need additional effort to start doing anything


1b - I do not work as well as before


2 - I need extra effort to force myself do something


3 - I can't work at all





0 - I sleep as usual


1 - I wake up unusually tired in the morning


2 - I wake up 2-3 hours earlier than usual, and it is hard for me to fall asleep


3 - I wake up earlier than usual and sleep for no more than 5 hours





0 - I get tired no more than usual


1 - I get tired easier than before


2 - I get tired doing anything


3 - I am too tired to do anything





0 - my appetite is same as before


1 - my appetite is not as good as before


2 - my appetite has become much worse


3 - I have no appetite at all





0 - if I lost weight, it was not much


1 - I lost more than 2 kg of weight


2 - I lost more than 4 kg of weight


3 - I lost more than 6 kg of weight





0 - I think about my health not more often than usual


1 - I am concerned because of pain or other sensations in the body, gastric disturbance, or constipation


2 - I am very focused on what I feel and how I feel, and thinking about something else is hard


3 - I am completely immersed in my feelings





0 - I havent noticed any changes in my sex life


1 - my sexual activity is lower than before


2 - my sexual activity has decreased significantly


3 - I lost sexual activity






Indicator for each category is calculated as follows: every paragraph on the scale is scored from 0 to 3, in accordance with the increasing severity of symptoms. The total score ranges from 0 to 62, and is reduced in accordance with improvement of the condition.






Total score for all categories is taken into account when interpreting data.



0-9 - absence of depressive symptoms


10-15 - mild depression (subdepression)


16-19 - moderate depression


20-29 - significant depression (moderate severity)


30-63 - severe depression


Gradual evaluation of the severity of 21 symptoms of depression


Paragraphs 1-13 - cognitive-affective subscale (C-A)


Paragraphs 14-21 - subscale of somatic manifestations of depression (S-P)