NEWS ON THE ETIOPATHOGENESIS OF SCHIZOPHRENIA

1 . G E N E R A L C O N S I D E R AT I O N S A B O U T SCHIZOPHRENIA

Definition
Schizophrenia is the disease in which the individual is being separated at the highest level of integration of his personality, which defines his status as a human being (1) ?. Schizophrenia is a mental disorder characterized by the presence of a symptomatic polymorphism, grouped into several nosological entities, symptoms that fall mainly in the category of perception, thinking, affectivity and behavior disorders. The symptoms vary during the patient’s life, being is different from one patient to another, the effects of the disease are long-term effects and the evolution is severe.

Epidemiology
The prevalence of schizophrenia, if we refer to the general population, is of 1%, ranging between 1.4% and 1.6%. Most studies taking into account the ethnic factors have showed no differences in terms of the prevalence of schizophrenia in different cultures.
The incidence of the disease is of approximately
0.15‰/year (ranging between 0.16‰ and 0.42‰), with a higher rate in the industrialized countries, in people with a lower cultural level (1, 2).
Studies have shown that the genetic predisposition for schizophrenia in monozygotic twins shows a 33-78% concordance, while in fraternal twins it is of 8-28%. The difference between these results also lies in the fact that in the monozygotic twins, the genetic factors are also accompanied by the ambient factors (it is more likely that they live in the same environmental conditions). Because in monozygotic twins no 100% concordance has been found, we can say that it is not the disease that is being transmitted, but the vulnerability to develop it. The next in kin relatives of a patient with schizophrenia are at risk of developing the disease 5-10 times higher than other people who do not have a genetic load of this kind. If both parents are schizophrenic the child’s risk to suffer from this disease is of approximately 35%. In the adopted children coming from families with a schizophrenic member, there is an increased risk of developing this disease or another disease in the category of schizophrenia (3).
Regarding the incidence depending on sex, the ratio is of approximately 1:1 M:F. The difference lies in the onset of disease, which in males it ranges between 15 and 25 years, while in females it ranges between 25 and 35 years of age. This could be due to the hormonal differences and to c e r t a i n p r e m o r b i d f a c t o r s , s u c h a s p e r i n a t a l complications, which are more often reported in males, and also the marital status (3).
The onset of schizophrenia occurs in late adolescence and early adulthood. It is estimated that the age for the onset of schizophrenia ranges either between 15 and 44 or between 15 and 54 years of age. The age for the onset of schizophrenia is usually in late adolescence or early youth, most often under the age of 45. apparently, there have been cases of schizophrenia after this age too, but it is more difficult to diagnose it because the clinical picture changes, given the development stage at this age (1, 3).
The risk factors that may be incriminated in causing the disease might be:
a) demographic – ethnicity, age, gender
b) predisposing – genetic, intrauterine complications (viral infections – influenza virus, influenza, retroviruses; nutritional deficiencies, eclampsia, toxemia); birth complications – prolonged labor, hypoxia, trauma, prematurity; postpartum complications – viral infections c)precipitating – social factors (stressful events), the phenomenon of immigration and the minority status, urbanization and industrialization
The comorbidities associated to schizophrenia are:
-the common somatic diseases: diabetes, metabolic syndrome, coronary heart disease, atherosclerosis, myocardial infarction, osteoporosis, TB, cancer;
-the rare genetic diseases: basal ganglia calcification, stenosis of the aqueduct of Sylvius, agenesis of the corpus callosum, Marfan syndrome, acute intermittent porphyria;
-alcohol or drugs (marijuana, cocaine), caffeine, antiparkinsonians, stimulants, benzodiazepines (1,2,3). The mortality is higher in younger patients, in patients suffering from this disease for less than 5 years, the causes of the death being either unnatural, especially suicide, accidents, homicide or natural (cancer, heart diseases, ischemic diseases, respiratory diseases) (1).
The main means for mortality in schizophrenia is suicide. The suicide rate in schizophrenia is of 10% and accounts for values that are ?1.6 times higher than the in the general population of the same sex and age. The suicide mainly occurs if the following risk factors are present: white race, male gender, social isolation. It appears more frequently in patients with depressive symptoms, in those who are aware of their deteriorated condition and of the reduced possibilities of becoming healthy again.

1.HYPOTHESES ON ETIOPATHOGENESIS

1.1 Biochemical hypothesis
2.1.1 Neurotransmitters
The neurotransmitters involved in the biochemistry of schizophrenia are:
-amines: dopamine, noradrenaline, serotonin, histamine;
-acetylcholine;
-amino acids: glutamate and gamma amino-butyrate;
-polypeptides: enkephalins, endorphins, endomorphin, dynorphins, cholecystokinin;
-other substances
The neurobiochemical mechanisms of schizophrenia, with pathological fluctuations at the neurotransmitter level, have been explored both directly in the postmortem brain tissue, and also in vivo by using neuroimaging techniques – the positron emission tomography (PET) and the single-photon emission computed tomography (SPET, S P E C T ) , e l e c t r o e n c e p h a l o g r a p h i c s t u d i e s , neurofunctional and neuronatomic studies through MRI – as well as indirectly, through assessments of metabolites in the cerebrospinal fluid, blood and urine; based on the effect of antipsychotics; based on the functional imaging studies on the receptors.
Currently the integrative theories on neurotransmitters are being accepted; they are based on the dopamine system interaction with other neurotransmitters like serotonin, glutamate, GABA, noradrenaline, neuropeptides, given the heterogeneous nature of schizophrenia (1, 2, 3).

Amines
Monoamines are regulatory molecules derived from the tyrosine amino acid.
Dopamine (DA)
It is present in the dopaminergic neurons: the weak fluorescent cells in the sympathetic ganglia, striatal, the medial prominence and other parts of the hypothalamus, the mesolimbic system, parts of the neocortex, terminations of neurons in the retina (4).
The arguments on the involvement of DA in schizophrenia are:
-the subcortical dopamine excess and the hyperactive subcortical mesolimbic dopamine system;
-the mesocortical prefrontal dopamine deficiency;
-the imbalance between the D1 and D2 receptors and the
glutamatergic system hypofunction;
-the effect of neuroleptics as D2 postsynaptic dopamine
receptor antagonists;
-the activity of the monoamine oxidase (MAO) in the brain tissue;
-effect of dopaminergic stimulants (amphetamines, cocaine, methylphenidate, ephedrine, levodopa);
-the presynaptic dopaminergic hyperactivity;
-the increase of the D2 receptors in the basal ganglia (5,6,7).
Noradrenaline (norepinephrine, NE)
It is present in the peripheral nervous system, in many postganglionic sympathetic terminations and in the central nervous system in: the cerebral cortex, hypothalamus, brainstem, cerebellum, spinal cord (4). Although the role of NE is not fully stated, the arguments on the involvement of the NE in schizophrenia are:
-the role of DA in the NE synthesis;
-the interactions between the dopaminergic and noradrenergic systems;
-the level of the NE brain metabolite (methoxy-hydroxy phenyl glycol, MHPG);
-the level of NE plasma metabolite (homovanillic acid, AHV) (8).
Serotonin (5 hydroxytryptamine, 5 HT)
It is present in the hypothalamus, the limbic system, cerebellum, spinal cord, retina. It derives from the tryptophan amino acid (4).
The arguments for the intervention of 5 HT in schizophrenia are:
-the hallucinogenic effect of the á-lysergic acid diethylamide (LSD), a substance with a structure that is close to 5 HT;
-the modulation of DA, due to the role of the 5 HT 2A receptors (especially), by which 5 HT inhibits the release of DA, mainly in the mesolimbic dopaminergic pathway: the antagonism of receptors by antipsychotics;
-the central serotonergic hyperactivity, with an increase in the plasma 5 HT;
-the cortico-subcortical serotonin imbalance with subcortical hyperactivation and prefrontal hypoactivation (8).
Histamine
It is present in the hypothalamus and other parts of the brain.
The intervention of histamine in schizophrenia is due to its interaction with the serotonergic system (9).

Amino acids
Glutamate
It is a derivative of the glutamic acid, an excitatory amino acid in the central nervous system, which is present in the cerebral cortex and the brain stem (4).
The arguments on the role of glutamate in schizophrenia are:
-the hypofunction of the glutamatergic system;
-the interaction between glutamate and DA under the influence of neuroleptics;
-the alteration of NMDA-type glutamate receptors, which get involved in the mesolimbic dopamine modulation;
-the excitotoxicity of the reactive oxygen species caused by the glutamate excess (10,11,12).
Gamma-aminobutyrate (GABA)
It is a derivative of the gamma-aminobutyric acid inhibitor amino acid (GABA), which is present in the cerebellum, the cerebral cortex, the neurons that mediate the post- synaptic inhibition, in many parts of the brainstem and the retina (4).
The arguments on the role played by GABA in schizophrenia are:
-the interaction between GABA and DA in the striatic and limbic systems;
-the GABA deficit caused by the DA excess;
-the stimulation of the GABA-ergic activity with excitotoxicity (10,13,14).
Opioid peptides
There are neuropeptides present, such as:
-enkephalins – in the gelatinous substance and other parts of the CNS and retina;
– ß e n d o r p h i n a n d o t h e r d e r i v a t i v e s o f t h e proopiomelanocortin – in the hypothalamus, thalamus, brainstem and retina;
-endomorphins – in the thalamus, hypothalamus, striatum;
-dynorphins – in the periaqueductal gray matter, the rostroventral medulla and the gelatinous substance (4).
The arguments on the role played by the opioid neuropeptides in schizophrenia are based on:
-the benefic effect of opioid antagonists (such as naloxone);
-the density of receptors in the postmortem brain tissue;
-the modification of opioids in the CSF.

Other peptides
Other peptides studied in schizophrenia, which would interact with the dopamine system are: cholecystokinin, vasoactive intestinal polypeptide, somatostatin, neurotensin, neuropeptide S, neuropeptide Y, peptide YY (1,4).
Cholecystokinin (CCK) is a neuropeptide present in the form of CCK-4 and CCK-8, in the cerebral cortex, hypothalamus, retina.
Vasoactive intestinal polypeptide (VIP) is present in the gastrointestinal tract from the stomach to the colon. Somatostatin (SS) is present in the median eminence of the hypothalamus and other parts of the brain, the gelatinous substance, retina.
Neurotensin is present in the hypothalamus and retina.
Neuropeptide S
Neuropeptide Y is present in the hypothalamus, autonomic nervous system, periaqueductal gray matter, adrenergic and noradrenergic neurons in the spinal cord. It is an inhibitor of glutamate. It interferes with stress, the circadian rhythm regulation and the control of the cardiovascular activity.
Peptide YY

Lipids
The endocannabinoids are endogenous products with an effect that is similar to that of marijuana. They act in the retrograde synaptic neurotransmission and reduce the production of GABA and glutamate at presynaptic level.

Other substances
Other substances that have been studied in the mechanism of schizophrenia are:
-phospholipids, which are present in the cell membranes, including phosphatidylserine, which is involved in the catecholamine transmission;
-G-proteins, in the parahippocampal gyrus and putamen, and coupled with the 5 HT catecholamines;
-acetylcholine and the enzymes involved in its formation and actions have been studied in the pontine tegmentum, hypothalamus, basal ganglia;
-prostaglandins that interfere in the modulation of the catecholamine brain systems (1, 4).
2.1.2. Oxidative and Nitrosative Stresses
The hypothesis of involving the oxidative stress in the pathogenesis of schizophrenia is based on:
-the changing of the oxidant / antioxidant balance in patients and on experimental models of schizophrenia in animals;
-the protective effect of certain antioxidants;
-the effect of antipsychotics in preventing the oxidative stress (amphetamine, haloperidol, chlorpromazine, ziprasidone, risperidone, clozapine, olanzapine) (15, 16,
17, 18, 19).
The hypothesis of involving the nitrosative stress in the pathogenesis of schizophrenia is based on:
-the decrease of the NO synthesis under the influence of phencyclidine (10, 20)
-the interaction between the circulating antibodies for schizophrenia and the NO synthesis (21)

2.2. Neurodevelopment Hypothesis
The neurodevelopment model emerged in the mid 80s and has the merit of having intensified research in terms of the neurobiological substrate of schizophrenia. In a nutshell, it is the occurrence of abnormalities in certain areas of the brain (due to factors that are genetic or acquired at birth) which causes other changes that are responsible for the clinical expression of schizophrenia. For example, the lesions in the prefrontal cortex may result in adolescence, when the cortex matures, to cognitive and behavioral deficits. At biochemical level, hypo-frontalisation triggers significant changes in the mediators in the subcortical levels with an increase in dopamine and glutamate, which account for the occurrence of psychotic symptoms (3).
The neurodevelopment hypotheses are based on the disturbances in the brain development during fetal and p r e n a t a l s t a g e s , a ff e c t i n g t h e s y n a p t o g e n e s i s , neurogenesis and myelination, the Wnt gene family, impairments which manifest themselves at puberty or afterwards (22, 23, 24).
The presence of brain structural changes has been correlated to the impaired premorbid functioning, the negative symptoms, cognitive deficits, weak response to antipsychotic treatment. The most modern neuroimaging (magnetic resonance) method has revealed: the global decrease in volume of the frontal cortex (the most affected area is the dorsolateral prefrontal cortex), the decrease in volume of the temporal lobe (amygdala, hippocampal gyrus, entorhinal gyrus, superior temporal gyrus), ventriculomegaly, an increase in volume of the basal ganglia (3).
The nutritional deficiencies, mainly vitamin deficiencies, may contribute to the poor neural development (25).
The asymmetry of the brain, as a development abnormality, has also been involved in schizophrenia (26). The role of the brain neurotrophic factor has also been studied in schizophrenia (27).

2.3. Neurodegenerative hypothesis
According to this, schizophrenia occurs as a result of an evolutionary chronic progressive process of neuronal brain degeneration (dopamine and glutamatergic neurons), which could be prevented by administration of neuroleptics (7).

2.4. Genetic Hypothesis
It has been believed for a long time that the occurrence of schizophrenia is related to a single gene and numerous linkage studies have been conducted for discovering it. At one time, it was thought that the responsible gene is on the long arm of chromosome 5, but subsequent studies have refuted this. The current hypothesis is that schizophrenia is transmitted not only by a single dominant gene, but that several genes with incomplete penetrance in certain regions of the chromosomes 1, 3, 4, 5, 6, 8, 10, 11, 12, 13,
17, 18, 21, 22, X are involved in the transmission of the disease (28, 29).
At the moment, a valid assertion is that the spectrum of schizophrenia is genetically transmitted, meaning that a certain genetic field from which the cases of schizophrenia shall afterwards be recruited under certain conditions. This spectrum includes several disorders (personality disorders, other mental diseases and even certain traits, such as creativity). In some cases of schizophrenia we can see – as a premorbid condition – the schizoid personality disorder, which has a pattern of shyness, the involvement in solitary activities, a certain concern mainly for philosophy and psychology, the tendency to social withdrawal (3).
The genetic hypotheses are based on the genetic vulnerability and the description of certain genes that are susceptible to the disease, such as gene RGS4 (30), the BNDF neurotrophic factor gene (31), neuregulin 1 (NRG1) (32, 33) and the interaction with nongenetic factors involved in neurodevelopment, such as toxins, viruses, other illnesses, as well as stressful life events (7,
34, 35, 36, 37).
So far no specific gene that is responsible for the occurrence of schizophrenia has been identified (7).

2.5. Neuroendocrine Hypothesis
It supports the role of the hypothalamic-pituitary-gonadal axis and the role of the estrogen hormones, which are involved in the fetal growth in the development of the aminergic brain network (38,39).
Other data show the role of the hypothalamic-pituitary- adrenal axis and of glucocorticoids and of the neuregulin 1 gene for schizophrenia (33).

2.6. Immunological Hypothesis
It is based on the existence of certain immunological deficiencies, the presence of autoimmune mechanisms, the increased level of IgA, IgM, IgE, the involvement of taraxein (21, 40, 41).

2.7. Hemodynamic and Metabolic Hypothesis
The hemodynamic and metabolic hypothesis is based on the increase of the cerebral blood flow in the left hemisphere and on the decrease in the frontal lobe, the disruption of the membrane phospholipids metabolism, the ATP decrease in the white matter. The research is based on studies with xenon 133 and PET (42, 43).
Changes in the cerebral metabolism has been highlighted by PET and SPECT studies, which have showed:
-the decrease in the cerebral blood flow in the frontal lobe (hypo-frontalisation) that is also correlated to the negative symptoms;
-the decrease in the cerebral blood flow in the temporal lobe;
-the decrease in the metabolism in the basal ganglia, its normalization after antipsychotic treatment has been considered as a response factor (3).

2.8. Seasonal Hypothesis
The seasonal hypothesis support the influence of the cold season on of births (late winter – early spring) and the increased incidence of viral infections, as the hypothalamus is affected by the herpes virus, retrovirus and influenza virus (44, 45, 46).
The seasonality of birth may also play a certain role in the onset of schizophrenia: children born in winter and early spring may be vulnerable due to the low temperature, the nutrient deficiencies due to the cold period and the various infectious agents (3).

2.9. Vulnerability Hypothesis
The increased vulnerability for schizophrenia is the result of the specific and non-specific risk factor predominance over the specific and non-specific protective factors (personal and social resources).
The following aspects contribute to the increased vulnerability:
-the genetic factors: sex chromosome abnormalities
-the biochemical factors
-the neurostructural factors
-the neurophysiological factors
-the somatic factors in the pre -, intra – and postnatal stages
-the social environment factors (1).

2.10. Stress Hypothesis
Studies showing the concordance between schizophrenia and the level of urbanism have revealed that in urban areas the disease onset rate increases due to stress and the multiple changes taking place in these areas, unlike the rural areas where there the social stability is greater and the integration of the population is higher (3).
Stressful life events, psycho-traumatizing events, have been shown to have a triggering role in the onset of schizophrenia, but only if there are biological or biochemical vulnerable conditions (2).
The concept of vulnerability – stress appeared in the 80s and considered as having a certain etiology resulting from the interaction between the biological factors (factors that are genetic or earned through perinatal complications) and the psychological factors. This way, the biological (genetic) factors would determine the disease genotype, while the psychological factors would account for the phenotype and would trigger they way it manifests itself. Therefore the final form of expression for schizophrenia is determined by the nature of vulnerability and stress versus the individual inner resources and the environmental support. The vulnerability is formed by genetic (constitutional) factors and biological factors resulting from the postnatal complications. The expression of vulnerability lies in several categories of factors: cognitive deficits, the attention deficit hyperactivity disorder (ADHD), poor eye contact, low relational ability (1, 2, 3).
Stress occurs in an unfavorable social environment marked by poverty, lack of education, ignorance; a reduced social network, addiction relationships, non- interactive relationships and due to negative life events. The types of stress include: chronic stress factors (low incomes, physical or mental disabilities, occupational difficulties) or acute factors (death, illness, loss, relocation) (3).

2.11. Psychosocial Hypothesis
The socio-economic status is one of the factors that are most often incriminated in fostering the onset of schizophrenia. It has been found that most of the patients come from low culture impoverished backgrounds, which involves the existence of stressful life events, the contact with various infectious agents, the inadequate prenatal care, low moral support for coping with negative life events. Another aspect of the social status is that it might actually be the result of the disabilities caused by this disease (1, 2, 3).
The marital status is also a vulnerability factor, as the increased rates of schizophrenia are present in single, unmarried or divorced people. And in this analysis we could assume that the unmarried status results after the onset of the disease and the subsequent relational difficulties (3).

2.12. Biopsychosocial Hypothesis
The biopsychosocial model created by George Engels considers that every individual contains, but at the same time is also contained in a multitude of systems related to one another. So there is a relationship of interdependence between the biological and psychological aspects, each of them shaping the other, but we should not forget that man is a social human being and this dimension must always be given to the other two, achieving thus the relevant balance (3).

2.13. Psychodynamic Hypothesis
Psychoanalytic Model
Freud was the first to create a psychodynamic model of schizophrenia, although he did not have any clinical experience with this disease. According to the structural theory developed by him, in schizophrenics there is always a conflict between desires and impulses represented by id and ego, always trying to adapt to subject to the reality. Therefore defense mechanisms appear and in schizophrenia they are mainly denial and projection mechanisms leading to the rupture of the contact with reality.
So if the same mechanisms appear in schizophrenia just as in neurosis, the difference lies only in intensity and, in addition, there is a regression of the patient to the most primitive stages of development (the pre- oedipal stage) and his fixation when psychotrauma occurs (1, 2, 3). Federn, a contemporary of Freud’s, was the first clinician in schizophrenia based on the psychodynamic model. He was more optimistic than Freud, believing that schizophrenia may benefit from psychoanalytic treatment. Federn nuanced the ego concept and described its boundaries. There is an external border which lies at the interface between the ego and the outer world and opposes the mental phenomena to the real ones, as well as an internal border separating the ego from the inner world, which mediates the conscious world from the unconscious. Therefore, schizophrenia would be an ego- related disease. The mitigation of the internal boundary would lead to a depression of the unconscious phenomena, while the weakening of the external boundary would lead to the disappearance of the distinction between real and the own mental (1,2,3).
Interpersonal model
Sullivan developed a theory that is based on the ego “feeling”, a concept first described by Federn, but used by Sullivan as a central phenomenon in psychopathology. According to it, the man is being perceived as a social human being who relates right from the beginning to the surrounding world in order to meet his needs. The process begins early, since the first years, when interacting with a highly anxiogenic mother may undermine the harmonious development of the ego, by creating an intense anxiogenic state. Later on, the other relationships occurring on this poorly erected edifice even induce a state of panic, which is lived extremely negatively, and which leads to the development of the defense mechanisms (dissociation, projection, sublimation). Hence, schizophrenia is being perceived as the person’s strategy to cope with terror by using his own means (defense mechanisms) for reconstructing his self-identity, even if it is done at mockery (1, 2, 3).
Transactional model
This model is based on the observation that the patient suffering from schizophrenia comes from a family of aberrant relational interactions and his psychopathology is determined by the experience of what he has seen and lived in his family.
Bateson and Jackson have highlighted the double link between the schizophrenic patient and a parent, where the latter demands a certain attitude, but at the same time he/she asks the child to have a certain conduct that cannot exist in the presence of the attitude shown (the “double bind” concept).
Ruth and Theodore Lidz have described various ways of intrafamilial relationships having an influence on the psychology of the child during his formation years:
-the split of the marital relationship despite the fact that officially they remain a couple;
-the strong controversy between the partners, although apparently they show a climate of understanding;
-the child has to act as one of his parents.
Wynne and Singer incriminate two other ways of intrafamilial communication:
– t h e v a g u e , i n e x p l i c i t a n d o f t e n i n t e r r u p t e d communication;
-a tense and hostile atmosphere that hides major conflicts. Other researchers have debated the emotional expression:
-an increased emotional expression;
-a negative emotional climate which consists in: criticism, intrusiveness, lack of support (1, 2, 3).

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