Current understanding of the etiology and pathogenesis of schizophrenia

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Introduction

Schizophrenia is a mental illness in which a person exhibits various positive (productive) symptoms, including hallucinations (seeing or hearing things that are not really there), delusional and catatonic states, mood changes, as well as negative symptoms such as apathy (lack of interest or motivation), problems with social adaptation. Schizophrenia can also cause disturbances in behavior and thought processes, problems with memory, attention and thinking¹.

The types of schizophrenia according to the ICD-10 classification include nine forms:

1. paranoid schizophrenia (F20.0);
2. hebephrenic schizophrenia (F20.1);
3. catatonic schizophrenia (F20.2);
4. undifferentiated schizophrenia (F20.3);
5. post-schizophrenic depression (F20.4);
6. residual schizophrenia (F20.5);
7. simple schizophrenia (F20.6);
8. another type of schizophrenia (F20.8);
9. schizophrenia unspecified (F20.9)².

Despite the fact that differential diagnostics of various forms of schizophrenia is difficult, it is possible to verify the form of the disease by collecting anamnesis, complaints and conducting a psychiatric interview taking into account the patient's mental status data. However, the etiology and pathogenesis are unclear, which complicates not only understanding the essence of the disease causes, but also the possibility of etiotropic and pathogenetic treatment.

The objective of the study is to create a literature review to summarize information on current issues in the etiology and pathogenesis of schizophrenia over the past 5 years.

Etiology of schizophrenia. Genetic background

About a thousand genes and more than 100 loci have been identified that contribute to the development of schizophrenia by triggering pathophysiological mechanisms, but each of them in isolation has little effect on the risk of schizophrenia. Among them, there are no genes that absolutely determine the disease. This creates pronounced genetic heterogeneity of the disease [1].

Chromosomal aberrations (genomic aneuploidy and mosaic autosomal aneuploidy) and point mutations in the form of nucleotide substitution and copy number variations (duplications, deletions, insertions, inversions) have been identified. Genetically determined pathogenetic mechanisms manifest themselves under the influence of provoking exogenous factors. In some cases, sporadic schizophrenia is not supported by heredity. Mutations in the genes 1q21.1 del/dup, 3q29 del, 7q11.23 dup, 15q11.2 dup, 15q13.3 del/dup, 16p13.11 dup, 16p11.2 del/dup, 17q12 del, 22q11.2 del/dup are more common in people with schizophrenia than in other people without this disease [2; 3]. At the same time, these genes also encode other mental disorders, so they cannot be called obvious determinants of schizophrenia. An increased risk of developing schizophrenia is associated with the PLXNA2 gene in the rs752016 locus, which controls brain semaphorins. They, in turn, are involved in controlling the process of axon formation, modulate plasticity and are responsible for neuronal regeneration [4]. Of particular interest is the ANK3 gene on chromosome 10, which encodes the protein ankyrin 3. This protein coordinates the work of the axon and the maintenance of the action potential. In people with schizophrenia, its expression is reduced [5].

It has been established that changes in the DRD2 gene are associated with problems in the dopamine system, and in GRIN2B it affects the work of the glutamatergic system [6; 7].

The role of the C4 gene in the etiology of schizophrenia was clarified based on the correlation of haplotype and variability. It turned out that the risk is higher, the more copies of the gene in the genome, "long" copies with HERV-K (a mobile genetic element of a retrovirus) and copies of the C4A isotype [8].

Mental and socio-cultural aspects of the etiology of schizophrenia

According to the psychodynamic theory of the schizophrenia development, the etiology of this mental illness is directly related either to the stage of an unformed ego and an attempt to restore it (according to Z.S. Freud), or to overprotection and rejection of the child (according to F. Fromm-Reichmann) [9].

The behaviorist theory of the origin of schizophrenia emphasizes learning by trial and error, reinforcement of the stimulus response. Bizarre reactions attract the attention of others or bring other types of reinforcement, thus increasing the likelihood that a person will resort to them again and again.

According to the cognitive theory, people with schizophrenia try to understand their strange sensations. The presence of voices, images and other hallucinations begins to frighten them. When they tell their friends and family about this, they are often not believed. The patients themselves believe that something is being hidden from them. This can lead to the development of delusions of persecution. The cognitive
theory of schizophrenia is considered one of the most convincing.

Family problems play an important role in the development of mental illnesses, including schizophrenia. Genetic predisposition can cause schizophrenia only in combination with severe emotional shocks, pathological amplifications and stress in the family or in the social life of the individual. When schizophrenia has already developed, social prejudices and problems in the family can worsen the situation or maintain symptoms [10].

Modern psychological researchers are paying more and more attention to the role of the family. It is believed that it is the violation of communication, both verbal and non-verbal, abuse, domestic violence, gaslighting, bullying that can influence the formation of erroneous views on their behavior in a growing child, which leads to the transformation of behavioral attitudes during the school period. When the child is again subjected to "family" rejection, the initially idiopathic symptoms are consolidated and transformed into truly organic symptoms based on dystrophy of the nervous structures of the peripheral nervous system and the brain, as well as dysfunction of transmitter systems [11].

Recent studies confirm that family factors play an important role in the development of mental health problems, including schizophrenia. Childhood trauma, abuse, and neglect may influence the onset of this disorder. For example, up to 65 % of people with schizophrenia report physical or sexual abuse in childhood. However, such abuse may also be associated with anxiety disorders and fears. It follows that the family factor of abuse, especially sexual abuse, must be compared with gender, age, stress factors, and genetic predisposition [12].

Neurotransmitter theories

The dopamine theory considers disturbances in the regulation of dopamine synthesis and, as a consequence, the presence of cognitive impairments, which are the substrate for the development of the schizophrenia symptom complex. Scientists have proven that blocking D2 receptors with neuroleptics suppresses the development of positive symptoms of schizophrenia [13]. Although the dopamine theory is the most reliable at the moment, it, like the genetic theory, is subject to criticism on various points. In particular, a number of studies refute the mediation between a decrease in dopamine secretion, its content in the striatum and the appearance of positive schizophrenic symptoms in the form of dysfunction of the cognitive reactions intermediates: attention, thinking, memory, etc. [14].

The pineal gland hormone, melatonin, has an insignificant effect on the development of schizophrenia symptoms, which is confirmed by some studies with melatonin as a marker and therapeutic agent. Authors who have studied the effects of melatonin on schizophrenia report conflicting results. Melatonin levels in the blood of patients with schizophrenia may be high, low, or unchanged. Melatonin is most often used therapeutically to improve sleep and reduce tardive dyskinesia [15].

Melatonin has a wide range of effects in the tissues of our body. In humans, it controls circadian rhythms, acts as a hormone, neuromodulator, cytokine, and mediator of biological responses. It affects the functioning of the brain, immune system, gastrointestinal tract, heart, kidneys, bones, and endocrine system. Significantly, melatonin can also help slow down aging and has a beneficial effect on cancer cells [16].

Neurodegenerative theory

This theory considers the etiology of schizophrenia in terms of pathological changes in the brain, revealed by MRI and CT. In the absence of changes in the neurotransmitter component, in schizophrenia one can observe the expansion of certain internal cavities of the brain (ventricles), a decrease in the size of some areas of the brain (frontal and temporal lobes), changes in the structure of the basal ganglia and hippocampus, and sometimes also a decrease in the volume of the cerebellum. This proves that schizophrenia is an organic disease with damage to the structures of the brain [17].

Viral theory

Some studies show that the RNA level of some viruses, such as HIV, herpes, and Epstein-Barr virus, may be associated with schizophrenia. Studying the relationship between HIV infection and mental disorders helps us understand the causes and mechanisms of schizophrenia. There is also an idea about a possible connection between a distorted immune response to Epstein-Barr virus and type W retrovirus (HERV-W) and the development of schizophrenia [17].

Immunological theory

The immunological theory links the presence of schizophrenia in patients with an increase in the level of interleukins, namely IL-2 and IL-10. A correlation has been found between the depression of T-helpers and the formation of autoimmune reactions that contribute to the development of schizophrenia. At this stage, the increase in the permeability of the blood-brain barrier in this disease is being actively studied [18; 19].

Hormonal theory

The concept of neurohumoral shifts underlies the hormonal theory. There is a hypothesis that changes in hormonal levels (reduced levels of sex hormones – estrogen and testosterone) trigger processes that lead to the development of schizophrenia. The relationship between neurotransmitter systems and hormones of the gonadal-pituitary hypothalamic axis, including estrogen, in schizophrenia has been proven. Estrogens have a neuroprotective effect, are able to modulate dopaminergic and other mediator systems involved in the pathogenesis of schizophrenia, and the estrogen-protective hypothesis, according to a number of authors, is valid for both women and men [20].

Theory of cortical disintegration

This theory is based on the presence of cortical atrophic disorders in patients with schizophrenia, accompanied by weakening or absence of gamma waves on the EEG, as well as changes in the P300 wave [21].

Leading pathophysiological mechanisms of schizophrenia

Modern research indicates that genetic predisposition plays a major role in the development of this disease. Various abnormalities associated with schizophrenia are found in genes that determine a variety of biological processes: proliferation and differentiation of nerve cells, their metabolism and functioning, as well as in genes involved in inflammatory, dystrophic, and autoaggressive processes. Thus, schizophrenia is a complex genetic disease caused by dysfunction of the dopaminergic, serotonergic, and glutamatergic systems. Schizophrenia can manifest itself in various situations, such as mental trauma and stress, with disruption of neurotransmitter metabolism.

According to the dopamine theory of schizophrenia, disruption of the regulation of dopaminergic neuron activity and changes in dopamine concentration in certain areas of the brain can lead to hallucinations and delusional thoughts. This is confirmed by the results of studies conducted not only with schizophrenia patients, but also with people suffering from alcohol or amphetamine psychosis [14].

There is an assumption that the glutamatergic and GABAergic systems may play a role in the development of schizophrenia. According to this hypothesis, problems with the NMDA receptor (a signaling protein) can disrupt the transmission of signals between cells, which leads to the appearance of schizophrenia symptoms. This can also increase dopamine activity in the brain. An increase in the amount of dopamine can aggravate the manifestations of schizophrenia. As a result of the unstable operation of these brain systems, problems with the control of excitability arise, which can lead to degeneration of nervous tissue and worsening of schizophrenia symptoms [21].

According to the theory of the influence of the situation in the family, contributing to the manifestation of schizophrenia, it is worth highlighting two pathogenetic mother’s role models: a) mother is an imperious paranoid personality; b) mother is an anxious "mother hen".

In the first case, the mother's personality encourages the child to be independent, strong and overcome difficulties. But these ideas about the mother and her prohibitions remain active in difficult situations, preventing independence. As a result, an adult can react regressively and return to helpless behavior from childhood – this is an unhelpful form of adaptation.

In the second case, when the mother is a sensitive personality type with certain psychological traits, she raises the child in such a way that he is a hypochondriac, uninitiative and dependent. When the child asks for help, the mother tells him: "Don't complain, don't cry, don't pay attention, figure it out yourself!" As a result, an unhelpful situation is formed, where the mother controls everything, and the child ignores his needs, which can lead to conflicts, isolation and problems in communicating with other people [11; 12].

According to the "stress diathesis", people with schizoid personality traits can react to stress more strongly and for a longer time. When they are exposed to prolonged emotional stress, it can activate a biological factor associated with disrupted signaling in the brain. As a result, symptoms of hallucinations and delusions may appear [12].

Scientific research is actively searching for the role of astroglia in the development of schizophrenia. It has been proven that this disease is characterized by a decrease in the activity of auxiliary brain cells. Astroglia stops multiplying, microglia decrease in size, and oligodendroglia begin to reverse development. When nerve cells are destroyed, the body does not start the recovery process, which is often the case with other nervous diseases [22; 23].

In people suffering from schizophrenia, changes and death of cells responsible for the production of myelin occur. This makes communication between nerve cells less effective. Clinically, this is manifested by apathy, rapid fatigue, sleep disturbances and impaired social interaction. Myelination disorders lead to problems in synchronizing brain activity and a decrease in connections between its different areas. Significantly, damage to the myelin sheaths can be present even before the manifestation of the disease [17].

Immunogenetic factors are of particular importance in the development of schizophrenia, these factors are associated with certain genes that control the immune response. These are the C4A and C4B genes, which affect the number of connections between nerve cells in the brain, especially in childhood and adolescence. Some studies have also shown an increase in the levels of certain substances in the blood and cerebrospinal fluid, such as IL-1, IL-2, IL-6 and TNF-α. One cannot ignore the fact that there is a change in the number of T- and B-lymphocytes, as well as associated autoimmune disorders, which are considered the main mechanism for the development of schizophrenia according to the immunological theory of the disease. Data on the correlation of leukocyte elastase with the appearance of negative symptoms of this disease indicate a significant role of immune pathology in the pathogenesis of schizophrenia [18; 19].

An important aspect of the pathogenesis of schizophrenia is the disruption of metacognitive processes (knowledge, experience, goals, strategy), which can lead to a breakdown in perception, problems in collecting information, and a sense of loss of connection with oneself and others. This can be an important factor in the development of schizophrenia, when patients feel a loss of their freedom and integrity. In some cases, patients are more concerned about the loss of meaning in their own identity than with psychotic symptoms [24].

In people with a genetic predisposition to schizophrenia, certain triggers, such as psychological trauma, stress, or social pressure, are required for the development of this disease [9].

Psychological trauma can greatly influence the development of schizophrenia in both men and women. For example, adverse experiences in relationships and sex can play a significant role. However, women tend to be more self-critical and maintain a clearer sense of self than men, and their ability to adapt to schizophrenia may be slightly better than that of men [25].

Conclusions

1. Schizophrenia is a genetically determined disease.
2. An important role in the etiology and pathogenesis of schizophrenia is played by transmitters – dopamine, serotonin, GABA. Violation of the synthesis of dopamine, serotonin, GABA or damage to the organs synthesizing them leads to the disease symptoms appearance. The role of melatonin in the pathophysiology of this disease is discussed, but there is no reliable research base.
3. Schizophrenia is often accompanied by organic damage, which is proven by MRI and CT of the brain. This is manifested by changes in the lateral ventricles, fourth ventricles and the cerebral cortex, namely the frontal and temporal lobes.
4. Schizophrenia may be caused by an autoimmune process, which is confirmed by changes in the cytokine profile, as well as the number of T- and B-lymphocytes.
5. The risk of schizophrenia increases with the presence of the following psychodynamic factors in the patient's life: psychological trauma in childhood and adolescence, sexual trauma, domestic violence, high levels of stress.

 

¹ Alfimov P.V., Erichev A.N., Lutova N.B., Maslenikov N.V., Mosolov S.N., Papsuev O.O., Tsukarzi E.E., Shmukler A.B. Clinical recommendations, Russian Federation 2021. Schizophrenia in adults. Russian Society of Psychiatrists, 2021; 119, available at: https://psychiatr.ru/down­load/4244?view=1&name=КР_+Шизофрения+25-11.pdf.

² ICD-10. International Classification of Diseases, 10th revision. Mental and behavioral disorders (F00–F99). Schizophrenia, schizotypal states and delusional disorders (F20–F29). version 2019, available at: https://mkb-10.com/index.php?pid=4160.

About the authors

V. V. Vanyukov

E.A. Vagner Perm State Medical University

Author for correspondence.
Email: vladvanuykov@mail.ru
ORCID iD: 0000-0002-2109-9447

4^th year Student of the Medical Faculty

Russian Federation, Perm

I. L. Gulyaeva

E.A. Vagner Perm State Medical University

Email: vladvanuykov@mail.ru
ORCID iD: 0000-0001-7521-1732

MD, PhD, Professor, Head of the Department of Pathological Physiology

Russian Federation, Perm

Е. R. Ganeeva

E.A. Vagner Perm State Medical University

Email: vladvanuykov@mail.ru
SPIN-code: 5842-2943

Senior Lecturer of the Department of Pathological Physiology

Russian Federation, Perm

О. S. Sukhanova

E.A. Vagner Perm State Medical University

Email: vladvanuykov@mail.ru

Clinical Psychologist, Lecturer of the Department of Psychiatry, Narcology and Medical Psychology

Russian Federation, Perm

Е. А. Zhvakina

E.A. Vagner Perm State Medical University

Email: vladvanuykov@mail.ru

4^th year Student of the Medical Faculty

Russian Federation, Perm

E. М. Minkhazeva

E.A. Vagner Perm State Medical University

Email: vladvanuykov@mail.ru

4^th year Student of the Medical Faculty

Russian Federation, Perm

Т. А. Baluyeva

E.A. Vagner Perm State Medical University

Email: vladvanuykov@mail.ru

4^th year Student of the Medical Faculty

Russian Federation, Perm

References

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