Schizophrenia

Schizophrenia is one of the major health problems in the world.

It is customary to consider schizophrenia as a separate nosological unit. In fact, it is rather a clinical syndrome, which can have a different etiology.

[1], [2], [3],

Epidemiology

During the life of schizophrenia, approximately 0.85% of people develop. Worldwide, the prevalence of schizophrenia is about 1%. The incidence rate is approximately the same among men and women, and also relatively constant in different cultures. The higher the prevalence among low socioeconomic classes in cities, perhaps because of the disabling effect leading to unemployment and poverty. Likewise, a higher prevalence among single people may reflect the effect of illness or precursors of the disease on social functioning. The average age at onset of the disease is about 18 years for men and 25 years for women. Schizophrenia rarely begins in childhood, but can be observed in early adolescence and later (sometimes called paraphrenia) age.

[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]

Risk factors

The emergence of psychotropic drugs and modern highly sensitive neurochemical methods made it possible to establish a connection between the function of the central nervous system and mental disorders. Study of the mechanisms of action of psychotropic drugs allowed to put forward a number of hypotheses about the role of certain neurotransmitters in the pathogenesis of psychosis and schizophrenia. Hypotheses involved the pathogenesis of these disorders of dopamine, norepinephrine, serotonin, acetylcholine, glutamate, several peptide neuromodulators and / or their receptors. The dopamine hypothesis of schizophrenia has remained dominant for more than a quarter of a century.

[18], [19], [20], [21], [22], [23], [24], [25]

Dopamine

Psychostimulants, including cocaine, amphetamine and methylphenidate, activate the dopaminergic system of the brain. Abuse of them can cause a paranoid psychosis, reminiscent of positive symptoms of schizophrenia. In patients with schizophrenia, psychostimulants are capable of provoking an exacerbation of psychosis. Conversely, there is strong evidence that the action of typical neuroleptics is associated with blockade of dopamine receptors. First, most typical neuroleptics are capable of causing extrapyramidal side effects, which can also develop with the death of dopaminergic neurons (such as Parkinson's disease). Secondly, binding studies with receptors have revealed a relationship between the clinical efficacy of typical neuroleptics and their affinity for dopamine D2 receptors. Moreover, it turned out that antipsychotic activity of neuroleptics does not depend on their interaction with other receptors: muscarinic, alpha-adrenergic, histamine or serotonin. All this suggests that the symptoms of schizophrenia are caused by excessive stimulation of dopamine receptors, presumably in the cortico-limbic regions of the brain.

However, a weak link in the dopamine hypothesis of schizophrenia is that the effect on dopamine receptors mainly affects positive symptoms and has little effect on negative symptoms and cognitive disorders. In addition, the primary defect of dopaminergic transmission in schizophrenia was not established, since in the functional evaluation of the dopaminergic system, the researchers obtained various results. The results of determining the level of dopamine and its metabolites in blood, urine and cerebrospinal fluid were unconvincing due to the large volume of these biological media, which leveled possible changes associated with limited dysfunction of the dopaminergic system in schizophrenia.

The increase in the number of dopamine receptors in the caudate nucleus in schizophrenia can also be seen as a confirmation of the dopamine hypothesis, but the interpretation of these changes is difficult, and they may not be so much a cause as a consequence of the disease. A more informative approach to assessing the state of the dopaminergic system is based on the use of ligands selectively interacting with D2 receptors and allowing their binding ability to be determined. Comparing the number of occupied receptors before and after administration of the drug, it is possible to estimate the ratio of the release and re-uptake of dopamine. Two recent studies using positron emission tomography (PET), based on this technique, for the first time provided direct evidence of the validity of the hyperdophaminergic theory of schizophrenia.

It is also important to measure the concentration of dopamine and its metabolites in the brain tissue after postmortem examination. But since the cells break down after death, the true concentrations of dopamine in tissues are often difficult to determine. In addition, the appointment of neuroleptics can also affect the results of postmortem biochemical research. Despite these methodological limitations, postmortem studies have revealed neurochemical differences in the brain of schizophrenic patients and those included in the control group. Thus, in postmortem brain studies, patients with schizophrenia have elevated dopamine concentrations in the left tonsil (part of the limbic system). This result was confirmed in several studies and is hardly an artifact (as the changes are lateralized). There was also reported an increase in the number of postsynaptic dopamine receptors in the brain tissue of schizophrenic patients who did not undergo antipsychotic therapy. These data confirm that the increase in the number of receptors is not a consequence of pharmacotherapy. In addition, there is evidence of an increase in the number of dopamine D4 receptors in certain areas of the brain, regardless of whether the patient was taking antipsychotics or not.

However, the dopamine hypothesis is not able to explain the development of the abulian and anhedonic manifestations of schizophrenia. As already mentioned, the complex of negative symptoms appears to be relatively independent of positive symptoms. An interesting fact is that dopamine receptor agonists can positively influence negative symptoms, while receptor antagonists contribute to its development in humans and model it in laboratory animals. So, although an elevated level of dopamine in the anterior cingulate cortex and other limbic structures can partly serve as a cause of positive psychotic symptoms, negative symptoms may be a consequence of a decrease in the activity of the dopaminergic system in the prefrontal cortex. It is possible that it is therefore difficult to create an antipsychotic drug that simultaneously corrects the hyperfunction of dopaminergic systems in certain regions of the brain and their hypofunction in others.

[26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]

Glutamatergic hypothesis of the development of schizophrenia

Glutamate is the main stimulant mediator of the brain. Interest in its possible role in the pathogenesis of schizophrenia arose from data on the N-MemuA-D-acuapmame (NMDA) receptor complex, the main subtype of glutamate receptors. Recent studies of the interaction between glutamatergic, dopaminergic and GABA -ergic brain systems have shown that phencyclidine in acute and chronic administration is a psychotomimetic that uncompetently blocks the NMDA receptor ion channel. With acute administration of phencyclidine, there are effects similar to the positive, negative and cognitive symptoms of schizophrenia. In addition, reports of prolonged exacerbation of psychosis in patients with schizophrenia confirm the psychotomimetic properties of phencyclidine. Long-term administration of phencyclidine causes a state of dopaminergic deficiency in the prefrontal cortex, which may be responsible for the development of negative symptoms. In addition, both phencyclidine and its analogue ketamine impair glutamatergic transmission. Observations of schizophreniform symptoms in persons abusing phencyclidine are also confirmed by studies in healthy volunteers, in whom ketamine caused transient, poorly expressed positive, negative and cognitive symptoms characteristic of schizophrenia. Like phencyclidine, ketamine caused distortion of perception. Thus, with glutamatergic deficiency, the same symptoms appear as in the hyperdophaminergic state, which resemble the manifestations of schizophrenia. Glutamatergic neurons through NMDA receptors are able to suppress the activity of dopamine-nerve neurons (directly or via GABA -ergic neurons), which can explain the relationship between the glutamatergic system and the dopamine theory of schizophrenia. These data support the hypothesis linking schizophrenia with the inadequacy of glutamatergic systems. Accordingly, in schizophrenia, compounds that activate the NMDA receptor complex may be effective.

The difficulty of developing drugs that stimulate the glutamatergic system is that excessive glutamatergic activity has a neurotoxic effect. However, it has been reported that activation of the NMDA receptor complex through its glycine site with the help of glycine itself or D-cycloserine alleviates negative symptoms in patients with schizophrenia, which is an excellent example of a possible practical application of the glutamatergic hypothesis.

The glutamatergic hypothesis reflects a major breakthrough in the study of biochemical disorders in schizophrenia. Until recently, neurochemical studies in schizophrenia were limited to studying the mechanisms of action of neuroleptics, which were developed empirically. With the growth of knowledge about neuronal organization of the brain and the properties of neurotransmitters, it became possible to develop a pathophysiological theory first, and then on its basis to create new drugs. Existing to date, various hypotheses of the origin of schizophrenia allow us to hope that in the future the development of new drugs will go more rapidly.

Other neurotransmitter and neuromodulatory hypotheses of the development of schizophrenia

The rich serotonergic innervation of the frontal cortex and limbic system, the ability of serotonergic brain systems to modulate the activity of dopaminergic neurons and to participate in the regulation of a wide range of complex functions allowed a number of researchers to come to a conclusion about the important role of serotonin in the pathogenesis of schizophrenia. Of particular interest is the hypothesis that an excess of serotonin can cause both positive and negative symptoms. This theory agrees with the ability of clozapine and other neuroleptics of a new generation blocking serotonin receptors to suppress positive symptoms in chronically ill patients resistant to typical neuroleptics. Nevertheless, a number of studies have questioned the ability of antagonists of serotonin receptors to attenuate the negative symptoms associated with psychosis, depression, or side effects of pharmacotherapy. Officially, these drugs have not been approved as a treatment for primary negative symptoms that form the underlying defect in schizophrenia. Nevertheless, the hypothesis that a possible therapeutic effect of antagonists of serotonin receptors (especially 5-HT2a has played a big role in the development of neuroleptics of a new generation.) The advantage of combined antagonists of D2 / 5-HT2 receptors is, rather, that the extrapyramidal side effects are less pronounced than in the higher antipsychotic activity, but since this improves compliance (patient willingness to cooperate), the treatment is more effective.

There are also hypotheses about the importance of dysfunction of noradrenergic systems in schizophrenia. It is believed that anhedonia is one of the most characteristic manifestations of schizophrenia, which consists in the inability to receive satisfaction and pleasure, and other deficiency symptoms can be associated with the dysfunction of the noradrenergic reinforcement system. However, the results of biochemical and pharmacological studies that tested this hypothesis turned out to be contradictory. As in the case of dopamine and serotonin hypotheses, it is suggested that in schizophrenia both a decrease and an increase in activity of noradrenergic systems can take place.

Generalizing hypotheses of the development of schizophrenia

The direction of future studies of schizophrenia is likely to be determined by complex models based on the synthesis of neuroanatomical and neurochemical hypotheses. An example of such an approach can serve as a theory that takes into account the role of neurotransmitter systems in the violation of connections between the cortex, basal ganglia and the thalamus forming subcortical-thalamo-cortical neuronal cycles. The cortex of the cerebral hemispheres through glutamatergic projections into the basal ganglia facilitates the implementation of selected actions, while suppressing others. Glutamatergic neurons stimulate intercalating GABAergic and cholinergic neurons, which in turn inhibit the activity of dopaminergic and other neurons. The study of neuroanatomical and neurochemical mechanisms of functioning of cortical-subcortical circles, considered in this model, served as a starting point for creating new hypotheses of the pathogenesis of schizophrenia. These models facilitate the search for neurotransmitter targets for new drugs, and also explain some features of the action in schizophrenia of existing drugs, for example, phencyclidine.

A modern neuroanatomical model was proposed by Kinan and Lieberman (1996) to explain the characteristics of the action of atypical antipsychotics (such as clozapine) compared to conventional drugs (eg, haloperidol). According to this model, the specificity of the action of clozapine is explained by the fact that it has a very specific effect on the limbic system, without affecting the activity of the striatum neurons, whereas typical neuroleptics have a significant effect on the striatum function. Other neuroleptics with similar properties (eg, olanzapine) may also have an advantage over traditional drugs. New antipsychotics (for example, risperidone and sertindole) do not limit their action only to the limbic system, like clozapine, but they favorably differ from typical neuroleptics in that they are less likely to cause neurologic disorders in therapeutic doses. Studies of the truth of this and other hypotheses will continue with the advent of new drugs similar to clozapine for pharmacological and clinical effects.

Pathogenesis

Patients with schizophrenia are shown certain groups of drugs, but the choice of the drug is often determined not so much by diagnosis as by the patient's symptoms and the nature of their combination.

Although distortion of perception and disorganization of behavior are different symptoms, they react to the same drugs - antagonists of dopamine D2 receptors. This justifies the joint consideration of these two symptom complexes in the discussion of antipsychotic therapy.

The mechanisms of development of negative symptoms in schizophrenia are associated with a decrease in the activity of the dopaminergic system in the prefrontal cortex, and not with its hyperfunction in limbic structures, which presumably underlies psychosis. In this connection, there are fears that drugs that suppress psychosis can exacerbate negative symptoms. At the same time, dopamine receptor agonists can reduce negative symptoms, but provoke positive symptoms. Negative symptoms are among the key manifestations of schizophrenia and are characterized by persistent disorders of the emotional-volitional sphere. Until now, there are no funds that would have demonstrably reduced these major manifestations of the disease. However, clinical trials of atypical antipsychotics have shown that they can reduce the severity of negative symptoms assessed using rating scales. The scales of SANS, BPRS, PANSS contain points that assess activity in school or at work, limiting social contacts, emotional detachment. These symptoms can be considered as general manifestations of the disease, diminishing with the weakening of psychosis, but may also be associated with side effects of neuroleptics (eg, bradykinesia and sedation) or depression (eg, anhedonia). Thus, a patient with severe paranoid delusions against neuroleptic therapy may become more sociable and less alert, and his emotional responses may become more alive as the paranoid symptomatology regresses. But all this should be seen as an easing of secondary negative symptoms, and not as a result of a decrease in primary affective-volitional disorders.

Many neuropsychological tests evaluating attention and information processing processes and suggesting a neuroanatomical interpretation reveal changes in patients with schizophrenia. Cognitive impairment in patients with schizophrenia is not directly related to the main symptoms of the disease and usually remain stable even with significant regression of psychotic symptoms. Violations of cognitive functions, along with primary negative symptoms, seem to be one of the important reasons for persistent disadaptation and a decrease in the quality of life. The lack of influence of typical neuroleptics on these central manifestations of the disease can explain such a high level of disability of patients, despite the ability of neuroleptics to effectively suppress psychotic symptoms and prevent their recurrence.

[37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51]

Symptoms of the schizophrenia

The concept of schizophrenia as a single disease appeared at the beginning of the XX century, when Emil Kraepelin suggested that paranoia, gebefrenia and catatonia are not separate diseases, but manifestations of dementia praecox. He also made a clear distinction between this form of mental illness and manic-depressive psychosis. This became possible after establishing the connection of a significant number of cases of mental illness with syphilis, which allowed to distinguish them from the rest of the group of patients with mental disorders. The discovery of etiology, methods of treatment and prevention of neurosyphilis became one of the main victories of medical science and gave hope that the causes of the main mental disorders will be found.

Eigen Bleuler (1950) proposed a new term for "schizophrenia" instead of the "dementia rheesoch" used earlier, arguing that the fundamental psychopathological phenomenon inherent in this disease was dissociation ("splitting") - both "inside" the thought process, and between thoughts and emotions. The term "schizophrenia" was an expression of this concept and, in turn, had a significant impact on its further development. The classical forms of schizophrenia (for example, gebefrenic, paranoid, catatonic, simple), which were subsequently supplemented with schizoaffective and latent, have so far been desig- nated for descriptive purposes in clinical practice, although there has recently been a trend towards the transformation of psychiatric terminology under the influence of the official American nomenclatures DSM-III and DSM-IV. However, the isolation of individual forms of schizophrenia has proved to be less fruitful, from the point of view of developing differential therapy or studying the etiology and pathogenesis.

ICD-10 mentions such symptoms of schizophrenia: delirium (whimsical, grandeur or persecution), frustrated thinking (intermittent or illogical flow of thoughts or incomprehensible speech), perception disorders (hallucinations, feelings of passivity, relationship ideas), mood disorders, motor disorders catatonia, excitement, stupor), personal decline and decline in the level of functioning.

During the life of schizophrenia, approximately 0.85% of people develop. In childhood, the symptoms of schizophrenia are manifested by the weakening of motivation and emotional reactions. Subsequently, a sense of reality is violated, and perception and thinking deviate significantly from existing norms in a given culture, which is usually manifested by delirium and auditory hallucinations. Often there are also visual and somatic hallucinations, disorganization of thinking and behavior.

Psychosis associated with a violation of the sense of reality, usually manifests in men aged 17-30 years, and in women - 20-40 years. The course and outcome of psychotic disorders are very variable. At the part of patients (about 15-25%) the first psychotic episode ends with complete remission, and in the next 5 years there are no psychotic disorders (however, with subsequent monitoring the proportion of these patients decreases). In other patients (approximately 5-10%), expressed psychotic disorders persist without remissions for many years. Most patients have a partial remission after the first psychotic episode, and subsequently exacerbations of psychotic symptoms are observed periodically.

In general, while the severity of psychotic disorders 5-10 years after the first episode reaches the plateau, the emotional-volitional impoverishment continues for a longer period. Progression of symptoms of schizophrenia is often the result of an increase in primary disorders associated with schizophrenia. These include autism, loss of efficiency, learning ability, low self-esteem and others. As a result, patients remain alone, can not find work, are subject to stress, which can provoke an exacerbation of symptoms and increase their functional defect. In addition, the diagnosis of schizophrenia still generates a negative reaction among the people around, which further limits the patient's possibilities. Although with age, there is a tendency to weaken the symptoms of schizophrenia and often improve functional status, it can not compensate for lost years of life and missed opportunities for the patient.

Connection of criminal action with schizophrenia

Wessely et al. In the course of studying the data of the Camberwell register, tried to answer the question: "Is schizophrenia connected with an increased risk and frequency of committing crimes"? Scientists come to the conclusion that people with schizophrenia, although not generally associated with people with an increased risk of criminal behavior, really are at risk compared with other mental disorders in terms of convictions for violent crimes. It was concluded that there is an increased risk of violence and, consequently, conviction by the court for violence among persons with psychoses, but this relationship is less obvious in the absence of comorbid substance abuse. In the survey of the Office of National Statistics on psychiatric morbidity among prisoners, the prevalence of functional psychoses in the year under review was 7% among convicted men, 10% among unconvicted men in pre-trial detention, and 14% among female prisoners, compared to a clearly comparable figure 0,4% in the general population. The results of this review may require a revision of the above results, since it is almost unbelievable that the difference in the prevalence of mental disorders between the prison population and the general population of this scale could be explained by the tendency of the courts to pass sentences on to mentally ill people. Of course, these results do not in any way indicate a causal relationship between crime and psychosis, they only indicate the existence of an association.

The connection of schizophrenia with violent crimes is usually given more attention than the ties of schizophrenia with other crimes. Taylor in his review of scientific research on this topic concludes that in persons suffering from schizophrenia and convicted of violent crimes, violent acts in the vast majority of cases occur after the onset of the disease. A study of the first episodes of schizophrenia shows that among patients with the first episode of the disease, more than a third a month before admission, there were manifestations of violent behavior, including a potential threat to the lives of others and bizarre sexual behavior. In many cases, prior to the first hospitalizations of these patients, there were appeals to the police, but after hospitalizations, charges were brought only in a small number of cases. Taylor investigated the possibility of schizophrenia in a consistent sample of the population of people in pre-trial detention in Brixton prison. Almost in 9% of cases, one of the forms of psychosis was noted and almost all had active symptoms of schizophrenia; Among those accused of committing a murder, a diagnosis of schizophrenia was present in 8% of cases. According to the report of the National confidential investigation of murders committed by persons suffering from mental illness, 5% of those convicted of murder had symptoms of psychosis. Unlike popular beliefs about people in psychosis, the victim most often becomes not a stranger, but a family member (a more general result obtained for violent behavior in the sample of the community in the study Steadman et al.).

Some specific symptoms of schizophrenia are correlated with violence. So, Virkkunen, when examining in Finland a group of schizophrenic patients guilty of severe episodes of violence, and a group of perpetrators of arsons, found that 1/3 of them committed crimes directly as a result of hallucinations or delusions; The remaining 2/3 committed crimes because of problems caused by stress in the family. The symptoms of threat / loss of control over the situation are directly related to violence. With symptoms that destroy the sense of personal autonomy and the ability to influence the situation, patients can consider their actions to counter the threats related to them ("rationality within irrationality") justified.

Psychotic patients with delusions who commit violent acts by virtue of their ideas are different from patients who do not commit violent acts, by the fact that they are engaged in the search for evidence in defense of their ideas, with the conviction that such evidence is found, as well as affective changes, in particularly depression, anger or fear, associated with their congestion delusions. In the Brixton studies, Taylor et al. With violent actions, the delusional ideas of passivity, religious delusions and delusions of influence were more reliably associated.

The risk associated with active symptoms of schizophrenia, including symptoms of threat / inability to control, increases significantly when substance abuse occurs. The role of the latter factor is emphasized by the data of the study by Steadman et al .: when exposed to this factor, the level of violence among recently discharged psychiatric patients was not higher than the level of violence in the general population. Hallucinations as part of the disease are most often associated with violence in the event that these are imperative hallucinations, or if falsely perceived tastes and smells are interpreted as "evidence" for delusions of control. The role of abnormal personal development in committing crimes by persons suffering from schizophrenia is worse than that (this is a comorbid condition or a consequence of the disease).

[52], [53], [54], [55], [56], [57]

Theories of symptoms of schizophrenia

The original concept of schizophrenia as an early-onset and steadily progressing throughout life neurodegenerative disease (dementia praecox) is currently rejected. Modern hypotheses consider schizophrenia as a neurodevelopmental disease associated with a violation of the development of the nervous system and progressing only in the early years, but not throughout life, which is better consistent with clinical observations. The dysentogenetic theory of schizophrenia makes it possible to understand the role of established etiological factors. Such risk factors for schizophrenia as a birth in winter, a positive family history, a complicated course of pregnancy and childbirth, can disrupt the development of the brain, early forming a predisposition to the disease. Observations of children with a hereditary predisposition, for example, those born by mothers suffering from schizophrenia, revealed a link between the presence of motor, cognitive and affective disorders and the subsequent development of psychosis. The question is debated whether psychosis is the result of the progression of the disease in childhood and adolescence or arises from the fact that the predisposition that emerged in the early years but remained stable appears during the period of growing up, under conditions of increased psychological stress. These theories do not exclude each other, since both suggest an early appearance of mild symptoms and the subsequent development of unfolded psychosis. It should be noted that after the disease has reached a psychotic level, neither the methods of neuroimaging, nor neuropsychological research, nor clinical observation, nor, finally, pathomorphological data indicate further progression of the disease.

In most patients, the negative symptoms of schizophrenia persist throughout life, and growing social maladjustment can be a consequence of the relationship between the sick individual and society. This can be explained at a very elementary level, for example, if we consider the employment problem. After a psychotic episode, it is difficult for a patient to return to his former life and his former occupation. Even in the absence of any symptoms, employers, co-workers, friends and relatives do not consider him a capable person. The unemployment rate among schizophrenic patients reaches 80%, although a large part of them remain functional. The importance of this factor is well shown in studies of socio-centric cultures in developing countries, where schizophrenic patients can maintain their social and professional status in a much less stressful environment. In these countries, the disease is more benign. A detailed discussion of the issues of the etiology and neurobiological basis of schizophrenia is made by Carpenter and Buchanan, Waddington.

It has long been noted that patients with schizophrenia are very heterogeneous in relation to the nature of the onset of the disease, the leading symptoms, the course, the effectiveness of treatment, the outcome. In 1974, an alternative hypothesis was proposed (Strauss et al., 1974), based on the data of transverse and prolonged clinical observations, which indicate a relative independence between positive psychotic symptoms, negative symptoms and impaired interpersonal relationships. The essence of the hypothesis is that these groups of symptoms have an independent psychopathological basis, and do not represent a single unified pathophysiological process. During the observation period there was a high correlation between the severity of the psychopathological symptoms belonging to one group and, conversely, there was no correlation between the severity of the symptoms belonging to different groups. These data have been confirmed in numerous studies, but with one addition. It turned out that hallucinations and delusions are closely related, but do not correlate with other positive symptoms (for example, disorganization of thinking and behavior). It is now generally accepted that the key manifestations of schizophrenia include distortion of the sense of reality, disorganization of thinking and behavior, negative symptoms and cognitive impairment. Negative symptoms of schizophrenia include a weakening of emotional reactions and their external manifestations, poor speech, reduced social motivation. Earlier Kraepelin described these manifestations as "the drying of the source of will." Differences between groups of symptoms are extremely important in the appointment of pharmacotherapy. Other clinical manifestations that are important from a therapeutic point of view include depression, anxiety, aggression and hostility, suicidal behavior.

For many years, the effect of drugs in schizophrenia has been estimated mainly because of their effect on psychotic symptoms or associated indicators, such as the length of hospitalization or remission. With the identification of the relative independence of different groups of symptoms, a comprehensive assessment of the effect of therapy on each of these groups has become standard. It turned out that standard antipsychotic therapy has virtually no effect on cognitive impairment and negative symptoms of schizophrenia. Meanwhile, these two groups of symptoms can have a decisive influence on the severity of the patient's condition and the quality of his life. Awareness of the limitations of the possibilities of traditional pharmacotherapy became the impetus for the development of new agents for the treatment of these manifestations of schizophrenia.

Schizophrenia is a chronic disease that can progress through several exacerbations, although the duration and characteristics of exacerbations may vary. Among patients with schizophrenia, there is a tendency to develop psychotic symptoms 12-24 months before seeking medical help. In the premorbid period, the patient may not be disturbed or the social competence may be violated, slight cognitive disorganization or distortion of perception is observed, the ability to experience pleasure (anhedonia) decreases and other general problems of coping with problems are present. Such symptoms of schizophrenia can be subtle and can only be recognized retrospectively or may be more noticeable with a violation of social, educational and professional functioning. In the prodromal period, subclinical symptoms can occur, including detachment or isolation, irritability, suspiciousness, unusual thoughts, distortions of perception and disorganization. The onset of the disease (delirium and hallucinations) can be sudden (days or weeks) or slow and gradual (over years). The type of schizophrenia can be episodic (with obvious exacerbations and remissions) or continuous; there is a tendency to increase the functional deficit. In the late phase of the disease, the patterns of the disease can be stable, the degree of disability can be stabilized and even diminished.

In general, the symptoms of schizophrenia as such can be divided into positive, negative, cognitive and disorganization symptoms. Positive symptoms are characterized by immoderate or distorted normal functions; negative symptoms - decrease or loss of normal functions. Symptoms of disorganization include thinking disorders and inadequate behavior. Cognitive symptoms are violations of information processing and difficulties in solving problems. The clinical picture may include symptoms from either one or all of these categories.

Positive symptoms of schizophrenia  can be divided into delusions and hallucinations or thinking disorders and inadequate behavior. Delusion is a false belief. In the delusion of persecution, the patient believes that he is annoyed, followed, deceived. In the delusion of the relationship, the patient believes that episodes from books, newspapers, lyrics or other external hints are relevant to him. In the delusions of insight or thought-taking, the patient believes that other people can read his thoughts, that his thoughts are transmitted by others, or that thoughts and motivations are invested in him by external forces. Hallucinations can be auditory, visual, olfactory, gustatory or tactile, but auditory hallucinations are by far the most common. The patient can hear voices commenting on his behavior, talking with each other or making critical and offensive remarks. Delusions and hallucinations can be extremely unpleasant for the patient.

Thinking disorders include disorganized thinking with incoherent, non-purposeful speech, with constant transitions from one topic to another. Violations of speech can range from mild disorganization to incoherence and meaninglessness. Inadequate behavior can be manifested childishly naive foolishness, agitation, not appropriate to the situation appearance and manners. Catatonia is an extreme variant of behavioral disorders, which may include maintaining a rigid posture and persistent resistance to movement, or aimless spontaneous locomotor activity.

Negative (deficit) manifestations of the disease are expressed in a form and include flattened affect, poor speech, anhedonia and unsociability. With flattened affect the patient's face looks hypomimous, with poor eye contact and lack of expressiveness. Poverty of speech is manifested by a decline in speech production, monosyllabic answers to questions that create the impression of an inner emptiness. An- donia can be a reflection of a lack of interest in activities and an increase in aimless activity. Unfairness manifests itself in a lack of interest in relationships with people. Negative symptoms often lead to poor motivation and a decrease in the focus of behavior.

Cognitive deficits include violations of attention, speech processing, working memory, abstract thinking, the difficulty of solving problems and understanding social interactions. The patient's thinking can become inflexible, the ability to solve problems, to understand other people's points of view and to learn from experience is reduced. Symptoms of schizophrenia usually disrupt the ability to function and significantly interfere with work, social relationships and self-care. The frequent result is unemployment, isolation, broken relationships and a decline in the quality of life. The severity of cognitive impairment largely determines the degree of general disability.

Suicides

About 10% of patients with schizophrenia commit suicide. Suicide is the main cause of premature death among schizophrenic patients, this partly explains why among people with schizophrenia, life expectancy is on average reduced by 10 years. Patients with a paranoid form of schizophrenia, late onset of the disease, and a sufficient level of functioning before the disease, who have the best prognosis, are also more susceptible to suicide. Since these patients retain the ability to respond to grief and suffering, they may be more likely to act desperately, based on a realistic understanding of the consequences of their illness.

Violence

Schizophrenia is a relatively small risk factor for behavior accompanied by violence. Threats of violence and small aggressive outbreaks are much more frequent than really dangerous behavior. Patients who are more prone to acts of violence include those who abuse drugs and alcohol, have delusions of persecution or imperative hallucinations, as well as those who do not take prescribed treatment. Very rarely, heavy-depressive paranoid patients who feel isolation, attack or kill those they consider to be the only source of their problems (for example, an authoritative, famous person, a spouse). Patients with schizophrenia can go to emergency departments with threats of violence or in order to get food, shelter and the necessary care.

Stages

Types of disease course: 

• Continuously-progredient, that is, chronic schizophrenia; 
• Paroxysmal schizophrenia, which in turn has subspecies 
  • Shuboobraznaya (paroxysmal - progredient);
  • Recurrent (periodic).

Stages of schizophrenia:

• The initial. It begins, as a rule, from asthenia, apathy and manifests by deep depression, psychosis, delirium, hypomania.
• Manifestation. The symptoms increase, the clinical picture freezes and becomes fixed.
• The final, the last stage. Symptomatology, as a rule, is deficient, the solidification of the clinical picture.

The degree of speed (progress) of the disease:

• Malignant schizophrenia (fast-probing);
• Paranoid schizophrenia (medium-graded);
• Sluggish form (low-grade).

[58], [59], [60], [61], [62], [63]

Forms

Five forms of schizophrenia are described: paranoid, disorganized, catatonic, residual and undifferentiated. Paranoid schizophrenia is characterized by delirium and auditory hallucinations with the preservation of cognitive functioning and affect. Disorganized schizophrenia is characterized by disorganization of speech, behavior, flattened or inadequate affect. In catatonic schizophrenia, physical symptoms predominate, including either immobility, or excessive motor activity and the adoption of pretentious postures. With undifferentiated schizophrenia, the symptoms are mixed. With residual schizophrenia, there is clear anamnestic information about schizophrenia with more vivid symptoms, followed by a long period of mild negative symptoms.

Some experts, on the other hand, classify schizophrenia into deficit and non-deficient subtypes based on the presence and severity of negative symptoms such as flattened affect, lack of motivation, and decreased focus. Patients with a deficit subtype are dominated by negative symptoms without taking into account other factors (ie, depression, anxiety, lack of environmental stimulation, side effects of drugs). In patients with a non-deficient subtype, delusions, hallucinations, and thinking disorders can occur, but they have virtually no negative symptoms.

[64], [65], [66], [67], [68], [69], [70], [71]

Diagnostics of the schizophrenia

There are no special tests to determine schizophrenia. Diagnosis is based on a comprehensive assessment of anamnesis, symptoms and signs. Often useful information from additional sources, such as family, friends, teachers and colleagues. According to the Manual on Statistics and Diagnostics of Mental Disorders, the fourth edition (DSM-IV), 2 or more characteristic symptoms (delusions, hallucinations, disorganized speech, disorganized behavior, negative symptoms) are needed for a significant part of the time during the month for the diagnosis, prodromal symptoms disease or microsymptomatics with social, occupational disabilities, lack of self-care should be evident throughout the 6-month period, including 1 month of obvious symptoms.

It is necessary to exclude psychosis due to other diseases or substance abuse through the study of anamnestic information and studies, including laboratory analyzes and methods of neuroimaging. Although some patients with schizophrenia have structural brain anomalies, they are not specific enough to have diagnostic significance.

Other psychiatric disorders with similar symptoms include some related schizophrenia disorders: transient psychotic disorder, schizophreniform disorder, schizoaffective disorder and delusional disorder. In addition, mood disorders can cause the development of psychosis in some people. Some personality disorders (especially schizoid) manifest symptoms similar to schizophrenic, although they are usually softer and not psychotic.

In the development of psychosis in the first place should try to establish its cause. If the cause is known, then treatment and prevention may be more specific. The fact that an accurate diagnosis is the key to effective therapy can be seen on the example of delusional symptoms, which can be a manifestation not only of schizophrenia, but also of temporal epilepsy, amphetamine addiction, manic phase of affective disorder. In each of these cases special treatment is required.

[72], [73], [74], [75], [76], [77], [78], [79]

Differential diagnosis

An algorithm for the differential diagnosis of schizophrenia can be found in the 4th revision of the American Psychiatric Association's DSM-IV Manual on Diagnosis and Statistics of Mental Illness. According to this algorithm, a patient with psychosis should first and foremost eliminate somatic diseases and the abuse of psychotropic substances. Then it should be determined whether the symptoms are caused by an affective disorder. If not, then, depending on the clinical picture, a diagnosis of schizophrenia or schizotypal disorder is made. Although the treatment of psychotic disorders of different genesis has its own characteristics, in all cases, as a rule, neuroleptics are used.

[80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92]

Treatment of the schizophrenia

Schizophrenia is clearly a condition requiring referral to psychiatric treatment. And here there is not necessarily a direct connection between psychotic experiences and a committed crime. It is enough that the subject is sick. In general, as practice proves, if the crime is not associated with positive psychotic symptoms, it is associated with a decrease in the patient's personality as a result of the disease. At the same time, it is, of course, possible to meet persons whose crime is a part of their life's criminal pattern, and which - as it turned out - they became ill with schizophrenia, but in general, people who need psychiatric treatment at this time need to offer such treatment. This does not always happen, especially in the absence of satisfactory inpatient services. If, on the one hand, the subject commits a crime, being in full remission, and this is part of his criminal "career", then he is responsible for his actions. Schizophrenia can be so severe that the subject can be found incapable of participating in the trial. This disease is the basis for reduced liability in cases of murder and may be grounds for the application of the McNaught rules.

The time interval from the onset of psychotic symptoms to the beginning of treatment correlates with the speed of the initial therapeutic response, the quality of the therapeutic response, and the severity of the negative symptoms. With early treatment, the patient usually responds more quickly and fully to treatment. In the absence of therapy during the first episode of the disease, 70-80% of patients develop a subsequent episode for 12 months. Long-term use of antipsychotics can reduce relapse rates by about 30% in one year.

The main goals of treatment are to reduce the severity of psychotic symptoms, prevent exacerbation of symptoms and related disorders of functioning, and also to help the patient to function at the highest possible level. Antipsychotics, rehabilitation with the provision of supportive care in the community and psychotherapy are the main components of treatment. Given that schizophrenia is a long and recurrent disease, teaching patients self-help skills is one of the important tasks of therapy.

Based on their affinity for specific neurotransmitter receptors and activity, drugs are divided into typical antipsychotics (antipsychotics) and second generation antipsychotics (APVPs). APVP can have certain advantages, concluding in a somewhat higher efficiency (although for some of these drugs, these advantages are controversial) and in reducing the likelihood of hyperkinetic disorders and other side effects.

Treatment of schizophrenia with traditional antipsychotics

The mechanism of action of these drugs is associated primarily with the blockade of dopamine D ₂ receptors (dopamine-2-blockers). Traditional antipsychotics can be divided into high, medium and low-potency. Highly potent antipsychotics have a greater affinity for dopamine receptors and lesser for a-adrenergic and muscarinic receptors. Low-grade antipsychotics, which are rarely used, have less affinity for dopamine receptors and a relatively greater affinity for adrenergic, muscarinic and histamine receptors. Various drugs are available in tablets, liquid form, short- and long-acting forms for intramuscular injection. The choice of the drug is based primarily on the profile of side effects, the necessary method of administration and the patient's previous reaction to this drug.

Traditional antipsychotics

Class	The drug (boundary)	Daily dose	Average dose	Comments
Aliphatic phenothiazines	Chlorpromazine	30-800	400 mg orally before bedtime	Prototype of low-potency drugs. Also in rectal suppositories
Piperidine	Thioridazine	150-800	400 mg orally before bedtime	The only drug with an absolute maximum dose (800 mg / day) - in large doses causes pigment retinopathy and has a pronounced anticholinergic effect. Additional caveats are included in the instruction in connection with the QTk extension
Dibenzoxazepines	Loxapine	20-250	60 mg orally before bedtime	Has tropic to dopamine D - and serotonin 5HT receptors
Dihydroindolones	Molindon	15-225	60 mg orally before bedtime	It may cause a decrease in body weight
Thioxanthenes	Tiothixen	8-60	10 mg orally before bedtime	High incidence of akathisia
Butyrophenones	Haloperidol	1-15	4 mg orally before bedtime	Prototype of high-grade drugs; there is haloperidol decanoate (IM depot). Often akathisia
Diphenyl butylpin-peridines	Pimozide	1-10	3 mg orally before bedtime	Approved only with Tourette's syndrome
Piperazine	Trifluoperazine Fluphenazine Perphenazine 2 ' 3	2-40 0.5-40 12-64	10 mg orally before bedtime 7.5 mg orally at bedtime 16 mg orally before bedtime	There are also fluphenazine decanoate and fluphenazine enanthate, which are depot forms (no dose equivalents)

QTk - 07 "interval, adjusted for the heart rate.

¹ It is now recommended to start the appointment of typical antipsychotics with a minimal dose and gradually titrate, increasing the dose to the required dose; recommended appointment before bedtime. There is no evidence that rapid dose build-up is more effective. There are / m forms for the treatment of acute conditions.

Traditional antipsychotics have some serious side effects, such as sedation, dulling of consciousness, dystonia or rehydration of muscles, tremor, increased prolactin levels, and weight gain (for the treatment of side effects). Akathisia (motor anxiety) is especially unpleasant and can lead to a lack of compliance. These drugs can also cause the development of late dyskinesia - involuntary movements, most often manifested by wrinkling movements of the lips and tongue, and / or the feeling of "twisting" in the hands or feet. The incidence of tardive dyskinesia is about 5% per year of taking medication among patients taking traditional antipsychotics. Approximately in 2% of cases, tardive dyskinesia seriously disfigures a person. In some patients, tardive dyskinesia exists indefinitely, even after stopping the medication.

Two traditional antipsychotics and one APVP are available in the form of long-acting depot preparations. These drugs are used to exclude the incompatibility of medicines. They can also help patients who, due to lack of organization, indifference or rejection of the disease, can not take their medications daily.

Depot-antipsychotics

Preparation 1	Dosage	Time to reach peak 2
Fluphenazine decanoate	12,5-50 mg every 2-4 weeks	1 day
Fluphenazine enanthate	12,5-50 mg every 1 to 2 weeks	2 days
Haloperidol decanoate	25-150 mg every 28 days (possibly every 3-5 weeks)	7 days
Risperidone microspheres S	25-50 mg every 2 weeks	35 days

¹ Introduced by intramuscular injection using Z-track technique.

² Time to peak after a single dose.

Since there is a 3-week delay between the 1st injection and the achievement of an adequate concentration in the blood, the patient should continue to take an oral antipsychotic within 3 weeks after the 1st injection. It is recommended to assess the tolerability before starting therapy with the oral form of risperidone.

Clozapine is the only APVP that has been shown to be effective in about 50% of patients with resistance to traditional antipsychotics. Clozapine reduces negative symptoms, almost does not cause motor side effects, has a minimal risk of developing tardive dyskinesia, but causes other undesirable effects, such as sedation, hypotension, tachycardia, weight gain, type 2 diabetes, increased salivation. Clozapine can also cause the development of seizures, this effect is dose-dependent. The most severe side effect is agranulocytosis, which can develop by example 1% of patients. Therefore, a frequent study of the level of leukocytes is necessary, and clozapine is usually used as a reserve drug in patients who do not respond adequately to other drugs.

Newer APVPs have many advantages of clozapine without the risk of agranulocytosis and are generally more preferable than traditional antipsychotics for the treatment of acute episodes and the prevention of exacerbations. New APVPs are very similar in effectiveness, but differ in side effects, so the choice of the drug is based on individual sensitivity and other characteristics of the drug. For example, olanzapine, which causes a relatively high risk of patients receiving long-term maintenance therapy, should be evaluated at least every 6 months. Evaluation tools such as the Scale of pathological involuntary movements can be used. Malignant neuroleptic syndrome is a rare but potentially lethal side effect characterized by muscle rigidity, fever, autonomic instability, and increased levels of creatinine phosphokinase.

Approximately 30% of patients with schizophrenia do not have a positive therapeutic response to conventional antipsychotics. In these cases, clozapine, an antipsychotic of the second generation, can be effective.

Treatment of schizophrenia with second-generation antipsychotics

Antipsychotics of the second generation act by blocking both dopamine and serotonin receptors (serotonin-dopamine receptor antagonists). APVP usually reduce positive symptoms; can reduce the severity of negative symptoms more than traditional antipsychotics (although such differences are controversial); can cause less cognitive coarsening; less likely to cause extrapyramidal (motor) side effects; have a lower risk of developing tardive dyskinesia; some APVP do not cause or cause an insignificant increase in the level of prolactin.

Scale of pathological involuntary movements

1. Observe the patient's gait on the way to the office.
2. Ask the patient to remove the chewing gum or denture if they interfere.
3. Determine if the patient is aware of certain movements.
4. Let the patient sit on a hard chair without armrests, holding hands on the knees, legs slightly diluted, and the feet exactly on the floor. Now, and throughout the survey, observe the entire body of the patient to assess movements.
5. Tell the patient to sit, holding hands without support hanging over the knees.
6. Invite the patient to open his mouth twice. Look at the movements of the tongue.
7. Instruct patient to stick out tongue twice.
8. Ask the patient to tap with the thumb on the other fingers of the hand for 15 seconds on each hand. Watch your face and legs.
9. Offer the patient to stand with their arms outstretched forward.

Evaluate each item on a scale of 0 to 4 on the degree of increase in severity. 0 - no; 1 - minimal, can be the extreme limit of the norm; 2 - easy; 3 - moderate; 4 - heavy. If the movements are observed only after activation, then they should be evaluated 1 point less than those that appear spontaneously.

Facial and oral movements	Mimic expressiveness of the face Lips and perioral region Jaws Language
Movement of the extremities	Arms Legs
Movement of the trunk	Neck, shoulders, thighs
General conclusion	The severity of pathological movements Insolvency due to pathological movements Patient awareness of pathological movements (0 - not conscious, 4 - severe distress)

Adapted from: ECDEU Assessment Manual for Psychopharmacology by W. Guy. Copyright 1976 by US Department of Health, Education and Welfare.

An increase in body weight, hyperlipidemia, an increased risk of type 2 diabetes mellitus are the main side effects of APVP. Therefore, before starting treatment with AOP, all patients should be screened for risk factors including personal / family diabetes burden, weight, waist circumference, blood pressure, fasting blood glucose, lipid profile. It is necessary to educate the patient and his family about the signs and symptoms of diabetes (polyuria, polydipsia, weight loss), including diabetic ketoacidosis (nausea, vomiting, dehydration, frequent breathing, blurred perception). In addition, all patients who start taking APVP should consult about nutrition and physical activity. All patients receiving APVP treatment need periodic monitoring of body weight, body mass index (BMI), fasting glucose and should be sent for special evaluation if hyperlipidemia or type 2 diabetes mellitus develops.

Second generation antipsychotics ¹

LASS	A drug	Dose limits	The average adult dose	Comments
Dibenzodiazepines	Clozapine	150-450 mg orally 2 times a day	400 mg orally before bedtime	The first APVP, which showed effectiveness in patients resistant to therapy. A frequent control of the level of leukocytes is necessary because of the risk of agranulocytosis; increases the risk of seizures, weight gain
Benzisoxazoles	Risperidone	4-10 mg orally before bedtime	4 mg orally before bedtime	May cause extrapyramidal symptoms in doses> 6 mg; dose-dependent increase in prolactin levels; a single APVP having a long acting injection form
Tienobenzodiazepines	Olanzapine	10-20 mg inside before	15 mg orally before bedtime	Comprombling, weight gain and dizziness are the most common side effects
Dibenzothiazepines	Quetiapine	150-375 mg orally 2 times a day	200 mg orally 2 times a day	Low potency allows for dosing over a wide range; nonanticholinergic effect. Titration of the dose due to the blockade of a-receptors is necessary, administration is necessary 2 times a day
Benzisothiazolylpiperazines	Ziprasidone	40-80 mg orally 2 times a day	80 mg orally 2 times a day	Inhibiting the reuptake of serotonin and norepinephrine, it may have antidepressant properties. The shortest half-life among new drugs; You need to take 2 meals a day with food. For acute conditions, there is a form for I / m administration. Low tendency to increase body weight
Dihydrocarostyril	Aripiprazole	10-30 mg inside before	15 mg orally before bedtime	Partial dopamine-2 receptor agonist, low tendency to increase body weight

APVP - second-generation antipsychotics.

¹ Control of weight gain and development of type 2 diabetes is recommended for this class of antipsychotics.

All second-generation antipsychotics are associated with increased mortality in elderly patients with dementia.

Treatment of schizophrenia with atypical antipsychotics began almost simultaneously with the beginning of the appointment of patients with schizophrenia typical neuroleptics.

Rehabilitation and social support services

Training of psychosocial skills and vocational rehabilitation programs help many patients work, shop and take care of themselves, manage their households, get along with others and collaborate with professionals in the field of mental health. Particularly valuable can be the maintenance of employment, when the patient is placed in a competing working environment and is provided by the mentor at the workplace to ensure adaptation to work. Over time, the mentor works only as a backup option when making decisions or for communicating with employers.

Social support services enable many schizophrenic patients to reside in the community. Although most patients can live independently, some need to live under supervision, where staff are present to ensure compliance with the medication regimen. Programs provide a step-by-step level of supervision in a different environment, ranging from 24-hour support to periodic home visits. These programs help to provide autonomy to the patient, while providing appropriate medical care reduces the likelihood of exacerbations and the need for hospitalization. Social care programs provide work at home to the patient or elsewhere and are based on a high staff-to-patient ratio; medical teams directly provide all or almost all necessary medical measures.

During severe exacerbations, hospitalization or crisis intervention in the hospital may be required, as well as involuntary hospitalization if the patient poses a danger to himself or others. Despite better rehabilitation and the work of social services, a small number of patients, especially those with marked cognitive deficits and resistant to therapy, need a long stay in hospitals or other supporting care.

Psychotherapy

The goal of psychotherapy is to develop a unifying relationship between the patient, family and physician so that the patient can learn to understand and self-help with his illness, taking medication according to doctor's prescriptions and more effective management of stress. Although a common approach is a combination of individual psychotherapy and drug treatment, there are few practical guidelines on this. The most effective is psychotherapy, which starts with addressing the basic social needs of the patient, providing support and education about the nature of the disease, promotes adaptive activity and is based on empathy and a proper dynamic understanding of schizophrenia. Many patients need empathic psychological support in adapting to the fact that the disease is often a lifelong disease that can severely restrict functioning.

In patients living with their family, psychoeducational family interventions can reduce the level of exacerbations. Supporting and protective groups, such as the National Alliance of Mentally Ill Patients, are often useful to families.

Forecast

During the first 5 years after the onset of the disease, functioning can be disrupted, social and professional skills are reduced, and disregard for self-care progressively increases. Severity of negative symptoms may increase, and cognitive functioning may decrease. Later, violations occur at the level of the plateau. There is some evidence that the severity of the disease can decline over the years, especially in women. Hyperkinetic disorders can develop in patients with severe negative symptoms and cognitive dysfunction, even if antipsychotics are not used.

The prognosis differs depending on the form of schizophrenia. Patients with paranoid schizophrenia have less severity of disability, and they respond better to treatment. Patients with a deficit subtype are usually more invasively-lidizirovany, have a worse prognosis, are more resistant to therapy.

Schizophrenia can be combined with other mental disorders. If it is associated with obsessive-compulsive symptoms, then the prognosis is especially bad; if with symptoms of borderline personality disorder, then the prognosis is better. About 80% of patients with schizophrenia suffer one or more episodes of major depression at some point in their lives.

During the first year after diagnosis, the prognosis is closely related to strict adherence to the prescribed psychotropic medication. In general, 1/3 of patients achieve significant and lasting improvement; 1/3 there is a definite improvement, but periodically there are exacerbations and residual disorders are observed; in 1/3 there are expressed and persistent symptoms of the disease. Only 15% of all patients completely return to a painful level of functioning. Factors associated with good prognosis include good functioning before the illness (for example, good learning, successful work), later and / or sudden onset of the disease, hereditary burden on mood disorders, rather than schizophrenia, minimal cognitive impairment, mild negative symptoms, paranoid or non-de fi cial form. Factors associated with a poor prognosis include early onset of the disease, poor functioning before the disease, familial burden of schizophrenia, a disorganized or deficit subtype with many negative symptoms. In men, the outcome of the disease is worse than that of women; women respond better to antipsychotics.

Alcohol and drug abuse is a significant problem in about 50% of schizophrenic patients. Single data suggests that marijuana and other hallucinogens can have extremely damaging effects on patients with schizophrenia, and should be prevented from using them by patients. The concomitant abuse of psychoactive substances is a significant predictor of poor outcomes and may lead to non-compliance with the medication regimen, repeated exacerbations, frequent hospitalizations, decreased functioning, loss of social support, including homelessness.

[93], [94], [95]