Some peculiarities of schizophrenia-related mental diseases etiological structure

Summary

The article reviews theoretical generalization of the current schizophrenia origin hypotheses, reasons the necessity to search new diagnostic-treatment approaches, studies concepts of origin of the schizophrenia-related mental disorders at the biopsychosocial level.

Key words: hypotheses, psychopathological dimensiones, schizophrenia spectrum.

Introduction

Schizophrenia-related disorders and schizophrenia itself make up a significant proportion of the whole psychiatric pathology - 17,3% and 12,9% respectively. According to the statistical data of the Public Health of Ukraine [31] the schizophrenia incidence makes up 0,068%. As shown in the stated data schizophrenia is one of the most common mental disorders and it significantly contributes to disabilities in psychiatry. The search of new methods of schizophrenia pharmaco- and psychotherapy variants, development of adequate approaches to the patients' rehabilitation are on the top of priority.

The problem of schizophrenia has a lot of aspects. The change of phenomenology and schizophrenia clinical course due to the therapeutic pathomorphism manifests itself by a large number of suppressed non- expanded and atypical psychotic forms with a subacute clinical course, negative symptoms and cognitive impairments as well as intolerance.

At the current stage of understanding of the schizophrenia pathogenic peculiarities and schizophrenia-related disorders the multidisciplinary approach to the psychiatric help becomes dominating.

Schizophrenia is a chronic mental endogenous progredient disease that emerges, as a rule, at a young age and is characterized by positive and negative symptoms.

The common feature of all the positive symptoms including hallucinations, delirium, affective, catatonic and hebephrenic symptoms is disorder of the unity of mental processes. Negative symptoms are manifested by a clear disorder of thinking purposiveness and personality cumulative changes represented by autism, alogia, anergy, anhedonia, apathy, abulia, affective flattening and disorganization of all the mental processes.

Within the framework of negative symptoms it is important to separate the primary negative symptoms related to the pathologic process itself and secondary symptoms appearing as a result of the neuroleptic therapy, hospitalism and co-occurring depressive disorders.

The cognitive symptoms include impaired attention concentration, disorders of the visual-spatial and abstract-acting function, verbal and working memory, verbal speed and motivational components.

At present there are a lot of theories of the schizophrenia origin. Having analyzed the main criteria for schizophrenia diagnostics starting from DSM-I (1952) to DSM-II (2013) it can be seen that all the classification data are based on the main theories of the schizophrenia origin: Kraepelin's theories about a chronic clinical course and un favourable development (1893), Bleuler's theories of segregation of mental functions (1911) as well as positive symptoms according to Schneider (1955). Thus, in DSM-I and DSM-II the main attention was paid to negative symptoms and social disadaptation. In 1980 in DSM- III Schneider's symptoms were considered as the key diagnostic criteria that narrowed the schizophrenia spectrum to progredient forms. Such an approach also remained in the following DSM versions where it was again decided to supplement the diagnostic criteria with negative symptoms as well as to refuse the development criteria of the disease first symptoms until 45 years [38, 43]. Six key schizophrenia diagnostic criteria remained also in DSM-V: delusional ideas, hallucinations, speech disorganization, expressed disorganized and catatonic behaviour, negative symptoms [10]. In DSM-V all forms of schizophrenia are excluded, that is planned to be made also in ICD- A lot of researches repeatedly emphasized the unreasonableness of separation of different schizophrenia forms due to low validity and prognostic value of establishment of these diagnoses [30, 39].

It should be mentioned that catatonia got a new special status in DSM-V, where it has a separate diagnostic column [46]. The developers consider catatonia as the secondary state in respect of some mental (schizophrenia-related disorders, bipolar affective disorder) and somatic (autoimmune diseases, hypoxic states, cerebral deficit of folates, etc.) diseases, side effects of antipsychotics and some other medicines. Thus, catatonic symptoms are encoded as comorbide, including “schizophrenia-related catatonia” [27].

In spite of the active use of neurophysiological terms in current publications, at present the American Psychiatric Association and the World Health Organization consider that there is no significant contribution of the neurobiological studies to the diagnostic criteria of DSM-V and ICD-11 [4, 28, 37]. The traditional approach of these organizations is that first mental disorders are diagnosed on the basis of clinical symptoms, and then pathophysiological mechanisms of their occurrence are studied.

For the progress of the future ICD and DSM classifications, which will be based on the achievements of genetics, neurobiology and behavioral sciences, it is necessary to analyze the scientific literature data that should help to implement these innovations as diagnostic criteria. However, the problem is that the necessary neuroscience data can not appear until the research space is limited by artificial clinical frames of diagnostic categories.

The main affecting components of the psychopharmacotherapy include neurochemical brain processes. In schizophrenia the spectrum of neurochemical disorders of these processes is extraordinary wide. But the clinical diagnostic assessment of the disbalance pathophysiological level of each of the neuromediator system in case of schizophrenia is extraordinary important in the structure of optimization of treatment and rehabilitation of schizophrenic patients. The revealed disorders of the neuromediator systems allowed to reconsider the paradigm of the antipsychotic therapy. The opinion stating that the efficacy of all the antipsychotic medicines is nearly the same was changed by the opinion that the psychopharmacotherapy should be chosen considering the patient's symptoms, its correlation with the neurotransmitter system disorder and choice of the antipsychotic taking into account its receptor profile and if required to add medicines of other groups [42, 43, 44].

Among neuromediators a great interest is shown in the dopaminergic system disorders. They were first discovered after introduction of chlorpromazine into the psychiatric practice and determination of its ability to block dopaminergic receptors [18, 19]. This hypothesis was confirmed by the revealed ability to block dopaminergic receptors in all antipsychotics, correlations between the severity of the antipsychotic effect and the degree of blockade of these receptors [14, 15]. An important contribution to its confirmation was also made by revealing the fact of the positive symptom development due to the use of psychostimulants (amphetamine-type, methylphenidate) and the psychosis development with paranoid symptoms in case of prolonged intake of psychostimulants [21, 24, 25, 26].

According to dopaminergic hypothesis, there is a dysfunction of the dopaminergic system - hypoactivity of mesocortical dopaminergic projections leading to the development of negative symptoms in schizophrenia and to the loss of control of inhibitory processes of mesolimbic dopaminergic activity and, consequently, to the subsequent development of positive symptoms [34, 46].

Based upon different levels of dopaminergic transmission in the neural paths and taking into account the detection of the activity of atypical antipsychotics in the action profile relating to the others, nondopaminergic systems, the hypothesis of the dysfunction existence in several neurotransmitter systems at the same time within the framework of schizophrenia was suggested [35, 44].

Recently scientists focus on the study of the glutamatergical system function. In case of schizophrenia the decrease of its activity in the frontal lobes of the brain can be observed, which is associated with negative symptoms of the frontal lobe schizophrenia. This can be explained by a wide representation of glutamatergic neurons (glutamate is the main excitatory neurotransmitter), as well as by the fact that glutamate and dopamine are in interrelated bonds: reduction of the dopaminergic transmission or blockade of dopaminergic receptors leads to the increase of the glutamate release, and, on the contrary, reduction of the glutamate release or blockade of its receptors leads to the increased dopamine release.

Disorders in the quantitative and functional state of glial cells were found, being one of the main components of the glutamate metabolism and synaptic plasticity regulators [16, 41]. The blockade of the NMDA-receptors and glial cell function impairment leads to the increase of the free glutamate level in the synaptic cleft, that, in its turn, causes disorder in the release of mediators of other neurotransmitter systems and, due to the increased excitatory activity and increase of the intracellular calcium level leads to the phenomenon of exitotoxicity and premature death of neurons [17].

Glutamate, as a neurotransmitter, is synthesized from glutamine in neurons and glial cells that also produce glycine [16]. Currently, 5 main glutamatergical paths involved in schizophrenia [26, 43] have been identified: cortical-truncal, cortical- basal, thalamic-cortical, corticothalamic and intracortical.

Neurotransmission of the gamma-aminobutyric acid (GABA) is closely related to changes in the glutamatergic system. Certain obtained data [22, 23] allowed to assert the presence of disorders in the GABA-ergic transmission in schizophrenia. The postmortem examinations revealed a decrease in the number of GABA-ergic neurons, including interneurons, and a decrease in the expression of GAD67 - glutamate decarboxylase-67, which participates in the synthesis of GABA, in the prefrontal cortex. Subsequent studies shifted the opinion from disappearance of neurons of this population to reduction of their function [42].

The interest in the study of the serotonergic function in case of schizophrenia is associated with the detection of the serotoninergic activity in the receptor profile of atypical antipsychotics. With the help of neurovisual studies the following changes were detected: increased binding of 5HT1a, decreased binding of 5HT2a and serotonin transporter activity in all the areas of the prefrontal cortex. At the same time, the use of preparations with an isolated ability to block 5HT2a or stimulate 5HT1a receptors did not lead to improvement of the schizophrenia clinical picture that allowed to formulate the hypothesis regarding the modulating effect of the serotoninergic system on the functioning of the dopaminergic transmission [19].

At present also such neuromediator systems as acetylcholinergic, noradrenergic and histaminergic are studied. The ability of acetylcholine to affect the level of release of all types of neurotransmitters, noradrenaline, was detected - mainly on the level of serotonin and glutamate release. A specific feature of the noradrenaline transporter is the ability also to transport dopamine, which is a precursor of the noradrenaline formation. The participation of these transmitters in the formation of cognitive and affective symptoms, a supervision system, a sleep-awake cycle and other rhythmic forms of mental activity [9] has been established.

Neurovisualization methods allowed to study the activity of the receptor binding when one or another antipsychotic is applied and, to a certain extent, the ratio between the influence on certain symptoms and the influence degree on certain types of receptors [34]. In particular, the blockade of the dopaminergic receptors of the second type is associated with the antipsychotic action itself - reduction of delirium, hallucinations, catatonic manifestations, mania, obsessions, and psychomotor agitation. This action is also associated with normalization of the motility of the gastrointestinal tract, antiemetic action, increased prolactin production and, consequently, gynecomastia, galactorrhea, sexual disorders and amenorrhea [6]. The blockade of the dopamine receptors of the third type is associated with the ability to activate, mitigate the negative symptoms, but to increase anxiety. The blockade of the alpha-adrenergic receptors of the first type is associated with sedation, cardiovascular disorders - hypotension and collapse, tachycardia, intracardiac conduction disorders and arrhythmias [29]. The blockade of histaminic receptors of the first type is associated with sedation, anti-allergic and antiscabious effect, increased appetite and hypotension. The blockade of serotonin receptors of the second type is associated with the anxiolytic effect, mitigation of both negative and positive symptoms of schizophrenia, sleep improvement without an expressed hypnotic effect, decreased aggressiveness, increased appetite, improved cognitive functions, decreased hyperprolactinemia level, antimigrainous effect, hypotension, and ejaculatory disorders. The blockade of acetylcholine muscarinic receptors of the first type is associated with a sinus tachycardia, dry mouth, constipation, paralysis of accommodation, pupil dilatation and increased intraocular pressure with possible provocation of the closed-angle glaucoma, urinary retention, memory impairment, confused consciousness and cholinergic delirium [40].

Robin Murray and Weinberger believed that there was some regularity in the manifestation of schizophrenia at the puberty age. Irwin Feinberg, in one of his papers (Feinberg, 1982), made arguments in favor of the fact that the changes in the brain occurring in the adolescent period can play a key role at the schizophrenia onset. Despite the different approach, they had same opinion that the study of the specifics of the brain structure processes at this age can disclose the elements that are impaired in schizophrenia.

In May 2016 an international team of scientists from the United Kingdom, China and Canada published the work evidencing the recovery of the grey matter volume in schizophrenic patients, including in the occipital area, where, on the contrary, there was an increase in grey matter [10, 45]. This is the first case when such possibilities of brain neuroplasticity were demonstrated.

In order to understand the nature of this phenomenon, it is necessary to find out the underlying biological substrate. The connection between neurons in the brain and in the peripheral part of the nervous system is provided by means of electrical and chemical processes. The neuron consists of a cellular body, dendrites, and axon. The axon ends in branching of smaller terminal fibers forming presynaptic or terminal patches. Terminal patches provide functional contact with other neurons, and the place of such functional contact is called synapse. Synapse is a narrow cleft, and the nervous impulse is almost always transferred through the synapse by chemical means using substances called neurotransmitters. The neurotransmitters are produced in the cellular body and accumulated in small spherical formations called synaptic vesicles. If a stimulus is present in the intracellular environment and extracellular space of the neuron the ionic concentration changes that leads to the nerve impulse propagation or the action potential. The electric charge extends over the dendrite and further - along the axon until it reaches the final plate of the axonal projection. Extensions, located at the axon end as well as along its length, contain synaptic vesicles with a neuromediator. The cytoplasm of each such extension also contains ferments taking part in the processes of synthesis and splitting of the mediator. Thus, each neuron has the ability to produce a neuromediator, a substance specific therefor. The neuromediator causes either depolarization (excitation) of the postsynaptic neuron, or hyperpolarization (inhibition).

Whether the postsynaptic neuron generates the action potential (i.e., transmits the impulse further) depends on the summation of the affects thereon from the presynaptic neurons. Each neuron can have hundreds of synapses, through some of them excitation signals can come thereto, and through the others - inhibitory ones. The neuron summates all these affects and, depending on the result, either generates or does not generate the action potential. When the action potential reaches the axon end, it triggers a chain of reactions that ends with the exit of the neuromediator from synaptic vesicles (exocytosis). After release the neuromediator penetrates through the synapse, spreads throughout the synaptic cleft and stimulates the receptors located on the dendrites and on the body of the other neuron. This neuron is called post-synaptic. In contrast to the presynaptic neuron containing only one type of neuromediator, the postsynaptic neuron has more receptors sensitive to different types of mediators. Furthermore, the receptors located on the presynaptic neuron (autoreceptors) are stimulated, leading to the change in the intensity of the synthesis of the neuromediator substance. If the neurotransmitter remained in the synapse for a while, this would reduce the number of messages that could be transmitted from one neuron to the other. Therefore, almost immediately after release, the neurotransmitter is inactivated. The mediator is inactivated by the enzymatic degradation of its molecules (typical of acetylcholine) or rapid return of neuromediators to the axonal end of the presynaptic neuron (reuptake).

Plasticity is one of the basic properties of the nervous system providing an adequate behavioral response of the organism to changing environmental conditions. It also provides such important functions as learning and memory.

The brain and the nervous system development can be described as a sequence of changes, each of which occurs at a certain age. At the stage of the cellular migration the axonal growth appears at the time when the migratory cells start getting cell processes. Axons are prolonged nerve cell processes, by which the information from the cellular bodies of some neurons is transmitted to the other neurons. The next important change in the nervous system development is the growth of dendrites. This growth does not start until the cells reach their final destination after migration. The process of the dendrite growth is more slowly than the process of the axonal growth, and is associated with a considerably larger branching and finer organization. Evidently an overabundance of dendritic branches occur at certain stages of the dendrite growth. Some of these redundant or unused branches will be eventually lost in the process of the so-called pruning or elimination. Other changes in the nervous system continue far beyond the juvenile age. So, despite the fact that myelinization begins in the intrauterine period already and reaches a high level until 15 years, myelin continues to be formed till 60 years. However, all these late changes are not related to growth. An important factor of these changes is the cell death.

The nervous system is also affected by such factor as the activity of the developing organism itself. The general principle characterizing the interaction between the environment and the nervous system development is the principle of functional confirmation. According to this principle, to "confirm" the usefulness of certain components of the nervous system, some form of stimulation or neural activity is required. Without such confirmation such components cease to function, and their growth and maturing stop.

Considering the dynamic system of current neurosciences, it is important to recollect the well- known discoveries of prominent scientists. For plastic changes occurring during the period of postnatal development, the morphological changes in the neocortex organization are more typical, including the formation of new bonds providing the most adaptive organism response [20]. The problem of development of the motor control central systems in the ontogenesis process is one of the urgent problems of neurobiology, that is important for understanding of the regulation principles and regularities of the motion activity formation. As noted above, it is known that the characteristic feature of differentiation in the central nervous system at the early stages of ontogenesis is the process of neuron death, which occurs along with the formation of new neuronal bonds. The existence of an excessive number of nerve cells in the early postnatal development is shown in different parts of the brain. Thus, the number of synapses in the visual cortex and spinal motorneurons exceeds the corresponding indices for adult animals in the limited period of ontogenesis

[30]. It is also shown that during the first week of the postnatal period several axons form synaptic contacts with each muscle fiber, while only one remains in adults. The redundancy of terminals is eliminated in the process of development due to competitive relationships, and those nerve cells which axons have not established a sufficient number of effective bonds, die [11]. Environmental factors play an important role in this process implementation and, first of all, the system-forming role of the sensory influx in the brain function maturation is observed. The increase or decrease of the sensory influx at the early development stages dramatically affects the morphophysiological organization of various brain structures, as well as changes the formation tempo of the animal behavioral reactions, affects the ability to learn [11]. The development of the motion system is closely connected with the development and activation of the body sensory systems. Several authors emphasize the special role of the ascending motor afferentation in the maturation process of functional characteristics of the central nervous system [22], which defines numerous aspects of the structural and functional brain maturation. On the other hand, immediately after the animal birth, a number of innate motor behavioral programs such as sucking is required, relatively independent of the external afferentation level and not requiring a detailed central control. Such motor behavior is based on the innate autogenic motor activity, which manifests itself during the prenatal development period and at the earliest stages of the postnatal ontogenesis [8]. Under the influence of an increasing flow of afferent impulses, the autogenic motor activity turns into a motor activity with reflex regulation. Thus, the development of the brain systems in the early postnatal ontogenesis is a complex multistage process which depends both on genetically determined factors and on the incoming sensory environmental effects.

The results of the analysis of the genetic material of almost 65 thousand people have shown that the risk of schizophrenia development increases with the presence of genetic variants associated with the process of the so-called synaptic pruning. Synaptic pruning is a process of synapse elimination that occurs between the early childhood and puberty onset. At birth, the human brain consists of about 86 (± 8) billion of neurons. The increase in the brain size after birth is provided by two factors: an increase of synaptic connections between neurons and myelinization of nerve fibers; but the total number of neurons remains unchanged. The synaptic pruning process is affected by environmental factors and plays an important role in cognitive processes. Upon reaching adolescence, the amount of synaptic connections decreases due to the synaptic elimination. Regressive processes regulate the excessive number of interneuronal compounds that are formed during neurogenesis, for the formation of specialized, functional brain architecture. In case of synaptic pruning there is a retraction of synaptic compounds that do not have functional expediency.

It is believed that the purpose of the synaptic pruning is removal of unnecessary neural structures of the brain; in the process of the human brain development the need for knowledge of complex notions becomes more relevant, and more ordinary connections formed in childhood, are replaced by more complex structures.

Pruning, which is associated with the development of cognitive processes, is known as pruning of small terminals ("cut" theory). Some terminals are competitively cut off according to the principle of synaptic plasticity - "use or lose". This means that frequently used synapses have strong connections, while rarely used synapses are eliminated.

In the study performed in 2007 by the scientists of Oxford University the researchers compared the brain of 8 newborns and 8 adults, assessing the size and evidential base collected on stereological fractionation. They showed that the average population of neurons in the mediodorsal thalamic nucleus area of adults was by 41% lower than that of newborns. However, by the number of glial cells, the opposite was observed: 36.3 mln on the average in the adult brain compared with 10.6 mln in newborns' specimens.

Based on the obtained data the scientists connected the manifestation of schizophrenia symptoms in adolescence with an increase of the synaptic pruning activity exactly during this period, and pointed out to the decrease of the number of interneuronal connections in schizophrenic patients as the disease progressed. The study also demonstrated for the first time that the C4 gene (complement system component - humoral protection of the body from foreign objects) plays a key role in the development of human brain, participates in the synaptic pruning, and is associated with the risk of schizophrenia development.

Based on the structure of the neural network in the cerebral cortex of adult primates, Lewis et al. [23] started a series of studies to discover how the neural network changes in the brain at the puberty age. Several interesting changes were detected in the dopaminergic innervation, as well as in the process of reduction of the number of excitatory inputs into the pyramidal cells. But the scientists were truly struck by clear changes in the distribution of different markers of candelabrum cells, especially by the scale of these changes at the puberty age, and by the coordinated marker refinement in their synaptic connections with pyramidal cells.

Neuron-candelabra are called so because of the characteristic form of their axonal branches. This subtype of GABA-ergic neurons of the cerebral cortex forms incoming connections only with the initial segments of the pyramidal cell axons, along with the place where the action potential is generated. Only candelabrum cells have an incoming access to this area, that means they can control the outcoming signal of pyramidal neurons. In vivo data have shown that candelabrum cells are capable of preventing the pulse generation by pyramidal neurons [16], although the in vitro study showed that in some conditions, their GABA-ergic action may be excitatory [21, 26].

From the presynaptic side, there was a decrease in the level of two proteins: parvalbumin and GAT1 - a protein providing the membrane transport of GABA. Both proteins take part in the regulation of GABA-ergic neurotransmission. A change in the number of one GABA (A) receptor subunit was observed on the postsynaptic side, which is selectively located on the primary segments of the pyramidal cell axons - the area receiving incoming signals from the candelabrum cells. The levels of both presynaptic markers, as well as receptors, fell sharply shortly before the period that in primates corresponds to the pubertal period in humans. The scientists' findings clearly pointed at the different nature of the inhibitory control effect on the initial segment of the axon in the pre- and post-pubertal periods. Paravalbumine detains intra-terminal calcium, performing the outflow function. The protein is slowly combined with calcium, located in the axon terminal. Usually, a certain amount of calcium remains in the intervals between the axonal discharges in the terminal, and in case of a fast series of discharges the so-called calcium transients are summated. The calcium accumulation increases the neuromediator release as the release depends on the amount of calcium in the axonal terminals. Thus, by lowering of the paravalbumine level the calcium "trap" is inactivated, which makes the transient summation possible and increases the GABA release when discharges go by series. If to consider the change in the parvalbumine level separately from other changes it can be concluded that the inhibitory influence on pyramidal cells carried out through the initial segments of their axons is fixed in the pubertal period, as the discharge series will intensify the GABA release.

Gary Westbrook considered the GAT1 transporter level decrease. He has shown that blocking of GABA transporters has a weak effect on the post-synaptic inhibitory flows, but in the case of single impulses. When the impulses go by synchronous series and release the mediator at the same time, the transporter blocking increases the duration of the inhibitory postsynaptic flows. That's exactly what happens in the synapses formed by the candelabrum cells. Consequently, it can be assumed that changes in the levels of both paravalbumine and GABA transporter result in the increased inhibitory control. Accordingly, the changes on the postsynaptic side can be interpreted on the contrary.

When trying to link disorders in the parvalbumine neurons with functional disorders in schizophrenia, it is important to note the following. Mark Howard's studies [18] show that the level of gamma activity in the prefrontal cortex increases proportionally to the level of the working memory load. The gamma activity remains high as long as the information is kept in the working memory, and decreases when the information has been used. If to consider the working memory functions (fixation, retention, reproduction and forgetting to "free space for another data set"), then the gamma-activity accompanies this process directly. The activity indicator grows with the information collection, remains high when it is kept and decreases immediately after its use. At the same time during the study it has been found out that the gamma-rhythm has a reduced frequency in schizophrenic patients when performing tasks for the working memory use. Considering these two observations it has been assumed that the disorders of the fast-discharge neurons form basis for the wave activity disorders, that, in turn, lead to the working memory disorders.

The reduced neurotrophic activity of TrkB receptors in the candelabrum neurons leads to a decrease in the GAD67 expression, that is, to the fall in the GABA level in the parvalbumine candelabrum cells of the prefrontal cortex. The presynaptic expression of GAT1 in the candelabrum cell cartridges decreases; the expression of the subunit of alpha-2 GABA (A) receptor in the initial segments of the pyramidal cell axons increases with the attempt to use the GABA "remnants" most effectively. But this compensatory reaction is not enough, consequently the inhibitory neurotransmitter is impaired, which synchronizes the descending activity of pyramidal neurons of the third layer, which projections lead to the other areas of the associative cortex. As a result, the synchronicity of the neural network discharges created by these cells is impaired. In its turn this leads to the oscillation decrease in the gamma-range during performance of the working memory tasks, that can be observed in schizophrenic patients. The synaptic pruning and evident decrease in the number of GABA-ergic compounds unmask disorders in these systems that develop in the early years.

In his first work, Karoly Mirnics (Mimics et al., 2000) described the lack of mRNA transcripts of the genes encoding the proteins involved in the processes of the neuromediator presynaptic release. If these two abnormalities in the gene expression reflect the early process, then the person will have impaired synaptic functions before the disease development already. The excessive number of synapses typical of childhood can compensate this decline in functioning, but upon reaching of the pubertal period the synaptic pruning will start two processes - the loss of the compensation ability and the synapse pruning with impaired functions. Thus, the described hypothesis partially explains the deviation in pruning and appearance of a clinical syndrome at the end of the pubertal period, as well as cognitive disorders in the prepubertal period.

After introduction of the neurovisualisation methods into practice the possibility of intra-vitam study of structural and functional features of the brain appeared, thereby bringing scientists closer to the mystery of the schizophrenia emergence. By the pneumocephalography and computed tomography methods the ventricular dilation was revealed in individuals with a long history of schizophrenia [48] in earlier scientific works already. The MRI appearance in 1973 allowed scientists to study a number of the brain characteristics in more detail. However, despite the significant progress on this issue, specific changes typical only of the schizophrenic patients' brain have not been detected by the MRI method yet.

Let's enumerate the most common nonspecific structural features occurring among schizophrenic patients. Among them, reduction of the total brain volume, the enlargement of the lateral and third ventricles [32], reduction of the grey matter in the middle and superior temporal lobes (more at the left), prefrontal cortex, thalamus and parietal lobe, including the supramarginal and angular convolution, cortex thickening in the occipital lobes [33]. These structural changes are already present in the disease onset, but can progress in the course of time [47]. Also interesting that the intensity of auditory hallucinations correlates with the reduction of the volume in the left primary auditory cortex, the left inferior supramarginal convolution, as well as the middle and inferior right prefrontal convolution [7]. The common nonspecific structural features among schizophrenic patients also include an increase in the volume of the caudate nucleus and other basal ganglia in response to the antipsychotic therapy [36]. An increase in the volume of basal ganglia is associated with the striatal neuron hypertrophy in response to the blockade of dopamine receptors in the nigrostriatal dopaminergic pathway with antipsychotics. Along with this, when replacing typical neuroleptics with clozapine, a reversible reduction of these structures to normal sizes can be observed [48]. It should also be mentioned that among schizophrenic patients who did not take neuroleptics, a decrease in basal ganglia could be observed compared with the norm [38]. The available data concerning the enlargement of the transparent membrane cavity [48], that may be evidence of the brain damage during its early development.

Certain mild structural brain anomalies can be found in the relatives of schizophrenic patients [37], that gives grounds to assume the presence of genetic factors responsible for the liability to disease. The last two facts speak in favour of the neurogenesis hypothesis associated with deviations in the nervous system development. The fact described above also remains important, it refers to the presence of structural anomalies at the disease onset already. Interesting data were also obtained when calculating the gyrification index (GI - the ratio of the total area of the cortex grey matter to the surface area of the cerebral cortex), where the brain folding ability is evaluated, that is, the ratio of convolutions and furrows [48]. In schizophrenic patients the increase of the gyrification index in the right dorsolateral prefrontal cortex [47, 49] has been revealed, that also speaks in favor of the neurogenesis hypothesis, as the establishment of furrows and convolutions occurs after birth and slightly changes throughout life.

With the help of the diffusion-tensor visualization (DTV, diffusion-tensor MRI), the fiber direction in the white matter can be visualized. The following features have been identified in schizophrenic patients using the DTV method. The impaired structure of the frontotemporal and frontal-parietal connections [20]. This pathology was revealed while studying the uncinate fascicle, that combines the frontal and temporal lobes, and the arcuate fascicle that connects the frontal and parietal lobe. Furthermore, these indices correlate with disorders of executive functions and verbal memory [33]. The correlation between the fractional anisotropy (fractional anisotropy (FA) indicates a relative decrease in the order of the parallel-oriented funicles) in the right inferior prefrontal cortex and impulsive behavior was established [2]. In one voxel-oriented study, there was a decrease in the FA revealed even in such areas of the brain as the corpus callosum, the left superior temporal cortex, parahippocampal convolutions, middle temporal cortex, inferior parietal cortex, middle occipital cortex, and the deep parts of the frontal lobe surrounding the genu of corpus callosum [6]. It is worth noting that the data obtained by the DTV method are not numerous and have a number of methodological limitations. However, even these data allow us to conclude that the white matter pathology plays an important role in the development of the schizophrenia clinical picture [33].

Particular attention in the schizophrenia development is paid to psychosocial theories, that consider the involvement of psycho-traumatic stress factors in the emergence of this disease from a theoretical perspective [1].

According to the concept of Eric Bern [5], each person represents a "set of stereotypes", due to upbringing peculiarities. They form the so-called "life scenario" - an individual life plan that is developed as the survival strategy and which model is laid up in the early childhood. Disorders in schizophrenia are considered as formation of the patient's personality structure in the form of the disease internal clinical picture with strong desadaptative internal introjects of parental figures, which psychotraumatic effect had a constant stimulation by the patient's dysfunctional environment, and a specific vision of reality that served as a function of psychological compensation from the frustrated need for contact with a close relative parental figure.

In such terms the anomalous salience theory combining the neurobiological basis of psychosis and the patient's subjective experience should be also considered. The term "salience" refers to the process by which an external stimulus, after reaching the human consciousness level manages its behavior due to its connection with the reward or punishment, that is, with a dopaminergic system, where dopamine is described as a "neurochemical switch" that transforms the nervous impulses of a neutral stimulus into a motivational-meaningful experience. S. Kapur transposed this concept into the field of psychiatry developing the abnormal salience theory, where appearance of psychotic symptoms is associated with chaotic and stimulus-independent dopamine release in the brain leading to increased attention and excessive importance of many stimuli [19]. In this case the phenomenon of a delusional idea, a delusional interpretation of reality and "perception selectivity" in schizophrenia is explained by the patient's attempt to explain his/her strange feelings and experiences.

Among the biological concepts of the schizophrenia origin the infectious and autoimmune ones can be distinguished. Thus, epidemiological studies confirm the role of the viral infection in the schizophrenia development to a certain extent. A viral infection of a pregnant woman, diseases having viral etiology in children of up to 5 years significantly increase the risk of schizophrenia. Thus, perinatal influenza infection leads to the limitation of reelin release by neurons regulating the cortico-hippocampal migration of neurons, which causes weakness of those brain structures that are struck by schizophrenia in the first place [13, 22]. The viral hypotheses of the schizophrenia genesis allow both direct effect of neurotropic viruses on neurons, leading to the destruction of these cells, and indirect. The displacement of the specific immunity, which can be observed in many viral infections, can be also seen in schizophrenia. Many experts point out the disbalance in the subpopulation composition of T-lymphocytes with a change in the ratio between the main sub-populations of T-cells, especially in the liquor. This may be evidence of a significant inhibition of both quantitative and functional parameters of the T-cell component of the immune response in schizophrenia [8].

The activation of the humoral component of the immune system is typical of schizophrenia and is manifested by an increase in the content of immunoglobulins of class G [13]. The connection of a number of immunobiological indices with the features of clinical symptoms and the pathological process degree was revealed. Thus, in the schizophrenia pharmacotherapy the normalization of a number of immunobiological indices can be observed, that some authors consider to be an indicator of the patients' reaction to the antipsychotic therapy, a marker of the therapy efficacy [3, 12].

Today, there are a lot of facts suggesting changes of the cellular and humoral immunity in schizophrenia. There are no doubts as to the interconnection of the immune and nervous systems represented by the neurohumoral system, and development of a new scientific direction - psychoneuroimmunology, studying the interaction features of these systems, is not coincidental. The immune system actively affects the central nervous system with cytokines that penetrate through the blood-brain barrier and directly affect the neurons. Astrocytes and microglias use these substances as mediators. The inflammation mediators, penetrating through the blood-brain barrier can assist in the movement of the microglial cells by chemotaxis to neurons with the subsequent release of lysosomal enzymes, resulting in destruction of these neurons. Some cytokines regulate the ability of astrocytes to limit certain effects of the inflammatory response, contribute to restorative processes and cell viability [13].

Based on the analysis of the genetic information, McCarroll and Sikar studied the region containing the C4 gene encoding the complement system protein. Unlike many genes, C4 has a high degree of structural variability: different people have different copies of this gene and the number of its genetic variants. McCarroll and Sikar have developed a new molecular method that allows to characterize the structure of the C4 gene in human DNA samples. They also studied the activity of the C4 gene in nearly 700 post mortem brain samples. The results of the study show that the structure of the C4 gene (DNA) can predict the activity of the C4 gene (RNA) in the brain of each person. They used information of the genome data analysis of 65 thousand people with and without schizophrenia to make conclusion about the activity of the C4 gene. As a result, researchers found out a significant correlation: in patients with a specific structural form of the C4 gene, the gene expression was increased and, in turn, a higher risk of schizophrenia was observed. The studies have shown that C4 protein plays a key role in the synaptic pruning during the process of the brain structure formation and is essential for functioning of the other protein (C3 component of the complement system), which serves like a kind of marker for elimination of the "marked" synapses. The obtained data also showed that the greater the C4-protein activity in the animal was, the more synapses were removed in its brain at the key moment of the development.

The results of the study help to explain to some extent why the cortex atrophy with fewer synapses is observed in the brain of schizophrenic patients compared to the brain of healthy people. The obtained data also allow to understand one of the reasons for appearance of cognitive dysfunctions in childhood due to the excessive activity of the synaptic pruning processes caused by the increased activity of the C4 component of the complement system.

schizophrenia mental disorder biopsychosocial

Conclusions and propsects of further developments

The concept of a multidisciplinary approach to the treatment of schizophrenia spectrum highlights the need for dynamic refinement of diagnostic evaluation on symptomatic, syndromologic, pathophysiological and etiological levels of diagnostics, complex applying of adequate psychopharmatherapy and psychotherapeutic counseling, correlation of possible positive and negative therapeutic pathomorphosis, interaction of used drugs, psychopharmacological anamnesis, as well as at high compliance.

The technical progress of the last decades allows to study schizophrenia spectrum diseases at different levels: biological (genetic, neurochemical, neurophysiological, neuroanatomical, neuroimmunological), psychological (neuropsychological, pathophysiological, researches of the structure of personality and mechanisms of its psychological protection) and social.

For the progress of the future classifications of ICD and DSM, it is necessary to analyze the data of scientific literature and base the classifications on the scientific achievements of evidence-based medicine, which should help to implement these innovations in the form of diagnostic criteria.

The obtained psychoneuroimmunological data of the normalization of a number of immunobiological parameters can explain their connection with the features of clinical symptoms and the degree of pathological process in the pharmacotherapy of schizophrenia, which can be an indicator of the patients' reaction to antipsychotic therapy and serve as a marker for the therapy effectiveness.

Subsequent studies in this direction will reduce ambiguous and controversial data, optimize the results of diagnosis and treatment of schizophrenic spectrum diseases.

List of references