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Reviews
Published: 2020-02-17

Modern approaches to the diagnosis and care of patients at the prodromal stage of schizophrenia

Bogomolets National Medical University
P.L. Shupyk National Medical Academy of Postgraduate Education
prodromal stage of the schizophrenia psychosis risk factors attenuated psychotic syndrome brief limited intermittent psychotic syndrome genetic risk of schizophrenia functional deterioration psychoactive substances treatment

Abstract

Background. The prodrome of psychosis is a period of pre-psychotic disorder that represents a deviation from previous human experience and behavior. It`s diagnosed partly retrospectively after the development of definitive symptoms and signs of schizophrenia. A prolonged untreated prodromal period is a precursor to an adverse disease course.

Method. The research material is modern publications devoted to the study of the clinical features of the prodromal stage of schizophrenia and the provision of specialized medical care. The research method is bibliographic and analytical.

Results. Modern diagnostic systems reveal early signs that are often observed in people at high risk of developing a psychotic disorder. Clinical factors of increased risk of transition to psychosis and very high-risk factors of psychosis in youth have been identified. Certain areas of painful change are stratified into neurotic, affective, cognitive, physical, behavioral, as well as subthreshold nonspecific and specific psychotic symptoms. Were selected types of psychosis` prodrome, depending on the severity of subthreshold psychotic symptoms.

The influence of cannabinoids on the central nervous system is carried out through a system of presynaptic endocannabinoid receptors, among which two types are distinguished: cannabinoid receptors of the first type (CB1) and cannabinoid receptors of the second type (CB2). These receptors are physiologically adapted to interact with two endogenous cannabinoids that are produced in the human body - with anandamide and 2-arachidonoylglycerol. Recent studies have shown that the level of anandamide in the cerebrospinal fluid of patients with schizophrenia is significantly increased. Moreover, in those who used cannabis occasionally, the level of this neurotransmitter was significantly higher than in those who used cannabis systematically or did not use it at all. Currently, there are three main scientific models of a possible association of schizophrenia and cannabis use: the “self-medication hypothesis”, the “causal model” and the “general factor hypothesis”. «General factor hypothesis» seems to be the most logical, since, indeed, the increased risk of both dependence on cannabis and the development of schizophrenia and other psychotic disorders of the schizophrenic spectrum can be associated with some common factor. Some genetic or social factors can act as this common factor, and in the group of people who are under the influence of this factor, the predisposition to psychotic disorders and cannabis use can have a synergistic effect on the emerging of clinically defined schizophrenia. International clinical guidelines recommend a few practical steps in monitoring patients in the psychosis` prodrome. But there are cautious about the use of antipsychotics if the patient does not meet the diagnostic criteria for a psychotic disorder. It`s advisable treating the psychosis` prodrome by a combination of antipsychotics and/or antidepressants, psychotherapy for patients and their families, as well as by omega-3 fatty acids. The prodromal phase of schizophrenia is the most optimal target for primary medical intervention, but its diagnostics and therapy require further scientific research and validation in actual clinical practice.

Conclusion. The prodromal stage of schizophrenia is the most optimal target for primary medical intervention; however, its diagnosis and therapy require further scientific research and confirmation in current clinical practice. In addition, a number of legal issues remain unresolved, because the provision of specialized medical care to people who have not been diagnosed with a mental disorder is currently in a certain legal vacuum.

Background

Psychosis prodrome refers to a period of prepsychotic disorder that represents a deviation from previous human experience and behavior. It is diagnosed in part retrospectively after the development of definitive symptoms and signs of schizophrenia. Prolonged untreated prodromal period is a warning of an unfavorable course of the disease.

Modern diagnostic systems detect the early signs that are often seen in people at high risk of developing a psychotic disorder. Clinical factors of an increased risk of the transition to psychosis as well as factors of a very high risk of psychosis in young people have been identified. Some areas of morbid changes are stratified into neurotic, affective, cognitive, physical, behavioral, and subthreshold psychotic symptoms of a nonspecific and specific nature. There are some types of psychosis prodrome depending on the severity of the subthreshold psychotic symptoms.

International clinical guidelines recommend several practical steps in monitoring patients with prodrome psychosis. But using antipsychotics if the patient does not meet the diagnostic criteria for a psychotic disorder should be treated with caution. Combination treatment of prodromal psychosis with a combination of antipsychotic and / or antidepressant medications, psychotherapy for patients and their families, as well as omega-3 fatty acids is advisable.

Methods and procedures

Modern publications devoted to the study of clinical features of the prodromal stage of schizophrenia and the provision of specialized medical care are used as research material. The research method is bibliographic-analytical.

Results

Diagnostic issues of the first manifestations of schizophrenia at the prodromal stage of its development

The prodromal stage of schizophrenia is potentially the most optimal target for primary medical intervention. But diagnosis and therapy at the prodromal stage require further research and confirmation in real clinical practice.

The term "prodrome" comes from the Greek word "prodromos", which means a harbinger of an event. In clinical medicine, prodrome includes early symptoms and signs of a disease, which precede the distinctive manifestations of the acute, fully developed disease. In essence, the term refers to a period of the prepsychotic disorder, which is a deviation from previous experience and human behavior. As in clinical medicine, prodrome is a retrospective concept that is partially diagnosed only after the development of definitive symptoms and signs.

The first psychotic episode is usually preceded by a prepsychotic prodromal stage that unfolds over several years. This is followed by a shorter psychotic prodromal stage. Prolonged untreated prodromal period is a harbinger of an unfavorable course of the disease [1].

The Australian Clinical Guidelines for Early Psychosis [2] propose a very interesting clinical staging model for the psychotic disorders presented in the prodrome stage and corresponding to the clinical stages 1a and 1b Table 1.

Clinical stage Definition Definition in staging model Targeted population Intervention
0 Increased risk of psychosis. There are currently no symptoms. Premorbid Adolescent relatives of the person with the disorder in the first degree. Primary prevention of FEP, for example: Improving mental health literacy; Family psychoeducation; Psychoeducation on psychoactive drug; Short training of cognitive skills.
Mild or nonspecific symptoms of psychosis, including neurocognitive deficits. Slight functional changes or reductions. Possible prodrome Adolescent screening. Appointment: Primary care physicians; School counselors. Secondary prevention of FEP, for example: Formal mental literacy; Family psychoeducation; CBT; Active reduction of psychoactive drug use.
1b Ultra-high risk of psychosis: moderate but subthreshold symptoms, with moderate neurocognitive changes and temporary or chronic decline in functioning (≥ 30% and / or <50% deterioration in SOFAS (PSP) in the previous 12 months). Possible prodrome Appointment: Educational agencies; Primary care physicians; Emergency department; Charitable organizations; School and university consultants. Secondary prevention of FEP, for example: Psychoeducation; CBT; Cessation of use or reduction of harm from psychoactive drug); Omega-3 fatty acids; Antidepressants or mood stabilizers.
2 The first episode of psychotic disorder is a complete threshold disorder with moderate symptoms, neurocognitive deficits, and decreased functionality (GAF 30–50), including acute and early recovery. Acute period and early recovery period Appointment: Primary care physicians; Emergency department; Charitable organizations; Institutions of specialized care; Drug dependency treatment. Early intervention for FEP: Psychoeducation; CBT; Working with the use of psychoactive drugs; SGAs; Antidepressants or mood stabilizers; Vocational rehabilitation.
3a Incomplete remission after the first intervention. Late / incomplete recovery Primary and specialized medical care Phase 2 intervention + additional emphasis on medical and psychosocial strategies to achieve remission.
3b Stabilized by treatment of exacerbation or recurrence of a psychotic disorder, with a GAF level below the first episode, residual and neurocognitive symptoms. Late / incomplete recovery Primary and specialized medical care Phase 3a interventions + additional emphasis on recurrence prevention and strategies aimed at "early warning signs".
3c Several relapses with objective deterioration of the clinical picture and the impact of the disease. Late / incomplete recovery Specialized medical care Intervention phase 3b+ a long-term stabilization.
4 Severe, persistent OR continuous disease with neurocognitive symptoms and disability criteria Chronic course Specialized medical care Phase 3c intervention, but with an emphasis on clozapine, other tertiary treatments, social activation despite disability.
Table 1. Clinical staging model for psychotic disorders (Australian Clinical Guidelines for Early Psychosis, 2010) Notes: FEP - First episode psychosis, CBT - Cognitive behavioral therapy, SGAs - Second generation antipsychotics

Modern classifications / diagnostic systems detect early signs that are often seen in people at high risk of developing a psychotic disorder. These include: main symptoms, attenuated positive symptoms, brief limited intermittent psychotic symptoms, features of schizotypal personality disorder, genetic risk associated with functional impairment, and general symptoms which are not characteristic of psychosis.

There is a special software, such as "A brief model of clinical prediction to predict the transition to psychosis in people at high risk," which allows by a minimum of signs to assess the likelihood of psychosis [3].

Currently, the predictability of the effectiveness of diagnostic systems of schizophrenia prodrome is between 25 and 40%. If additional factors are taken into account, the positive forecast value can increase to 68–80%. Thus, 20–75% of individuals may be erroneously classified as patients in the prodromal period of schizophrenia (false positive).

According to a contemporary view, any young person who has a decline in academic or professional function, social isolation, dissatisfaction and obvious distress or anxiety without a clear provoking factor should be carefully examined, especially if they have a family history of psychosis [4].

In addition to family history, clinical factors of increased risk of transition to psychosis include: greater severity and longer duration of attenuated positive symptoms; bizarreness in thoughts and behavior; paranoia; reduction of performance indicators of the general assessment for the previous year; cannabis or amphetamine use. A history of childhood trauma, hypersensitivity to psychosocial stressors, and dysregulation of the hypothalamic-gonadal axis have also been associated with the progression of psychosis. Moreover, the prodromal phase is a harbinger not only of psychosis, but also of the other mental illnesses, such as bipolar or obsessive-compulsive disorder.

The signs such as depersonalization, derealization, decreased reflection on other people and the environment, and intense reflexivity on oneself or other people are suggested to be considered as critical markers of psychosis progression. Another harbinger is the perception of the negativity of others in the form of increased sensitivity to rejection or shame. The presence of obsessive-compulsive symptoms during the prodromal phase is associated with a significant deterioration in functioning, accelerated transition to psychosis and an increased risk of suicide [5].

Based on the study of clinical manifestations of very high risk factors of psychosis in young people, there were stratified separate areas of painful changes [6]: neurotic symptoms (anxiety, nervousness); mood-related symptoms (depression, anhedonia, guilt, suicidal ideation, mood swings); symptoms of disorders of the volitional sphere (apathy, boredom, fatigue, decrease or loss of energy); cognitive impairment (impaired concentration, concern, dreaminess, blockage of thoughts, decreased disengagement); weakened or subthreshold psychotic symptoms (perceptual abnormalities, suspicion, change in feelings of self, others or the world around); behavioral changes (deterioration of role functioning, social isolation, impulsivity, strange, aggressive or destructive behavior); physical symptoms (somatic complaints, weight loss, poor appetite, sleep disturbances); other symptoms (obsessive-compulsive, dissociative).

The following criteria for identifying ultra-high risk of schizophrenia were also identified:

  • Young age (from 15 to 25 years);
  • Changes in subjective experiences and behaviors in recent months or within the last five years (which may fluctuate but progress).

In addition, the risk indicators of schizophrenia also include:

  • Subthreshold positive symptoms (not severe or persistent enough to meet criteria sufficient to diagnose a psychotic disorder).

or

  • A vignette of the psychotic symptoms in history (obvious psychotic symptoms reduced over seven days).

or

  • Genetic vulnerability, such as a schizotypal disorder or a first-degree relative with any psychotic disorder in history.

Decreased functionality (≥ 30% reduction in Social and Occupational Performance Rating Scales (SOFAS) at any time in the previous 12 months or prolonged poor functioning (SOFAS <50 in the previous 12 months) should also be considered as an indicator of risk.

Prodromal psychotic symptoms usually include a combination of relatively nonspecific and specific signs and symptoms.

Nonspecific signs and symptoms include low stress, anxiety (including social anxiety), obsessive-compulsive symptoms, depression and / or irritable mood, increased alienation and related difficulties in self-identification and "existential" problems, as well as vague somatic complaints.

Among the specific signs and symptoms there should be mentioned the combination of subsyndromal or subthreshold positive and negative symptoms. Positive symptoms include unusual or peculiar feelings, thoughts, beliefs, and occupations: transient ideas of reference, increased distrust or suspicion, grandiosity, impersonality or derealization, changes in auditory, visual, somatic, taste, and / or tactile sensations or perceptions. Negative symptoms are represented by demotivation, apathy, blunted affect, anhedonia, and social detachment or isolation [7].

Neurocognitive symptoms, usually of mild severity, are often manifested by the following set of symptoms: decreased concentration in the form of increased distraction and oblivisence, a certain disorganization of thinking and temporary confusion. Cognitive difficulties of this kind are quite nonspecific and can be observed in patients with a number of the other mental disorders of neuro-developed and neuropsychiatric difficulties, including attention deficit disorder, specific learning disorders and mood disorders. They are associated with a slight functional decline, which manifests itself in one or more areas: education, work, family and peer relationships, self-care, and a decline in quality of life.

A study by P. Gourzis et al. of 100 people with prodromal symptoms of schizophrenia compared with 100 people without a confirmed diagnosis of schizophrenia [8] showed the following: the average number of symptoms was 8 and 0, respectively, and the patients with schizophrenia primarily had developed symptoms indicating social, occupational and affective dysfunction, while symptoms of the control group included the magical meaning of thinking and mood disorders. The authors divided the initial prodromal symptoms into three categories: negative, positive-prepsychotic and positive-disorganizing. Patients with a "disorganized subtype" of schizophrenia mostly had negative symptoms in the prodromal state, and patients with a "paranoid subtype" of schizophrenia often had positive symptoms in the prodromal state. Observation of the course of symptoms from prodromal to psychotic state revealed that 58% of symptoms increased in intensity, 21% - remained unchanged, 5% - decreased; 3% of symptoms were transformed into affective disorders, 9% - in delusions, 1% - in hallucinations, and 3% of symptoms disappeared. The degree of dysfunction of patients depended on the subtype of schizophrenia, even in the prodromal phase.

Currently three main clinical varieties of prodromal subgroups have been described. The first is Attenuated Psychotic Syndrome (APS), when the patient has certain problems with communication, perception and unusual thoughts, but all these symptoms are subthreshold and do not reach a clinically significant level. They should occur at least once a week for at least one month and become progressively more severe during the year.

The second prodromal subgroup is characterized by Brief Limited Intermittent Psychotic Syndrome (BLIPS). In this case the patient also has intermittent psychotic thoughts in addition to problems with communication and perception. These bizarre beliefs or hallucinations should be present for a few minutes daily for at least one month, but not more than three months.

The last prodromal subgroup is the so-called Genetic Risk Plus Functional Impairment (G / D) group. At present, these individuals do not have psychotic symptoms even at the subclinical level, but they have been previously diagnosed with schizotypal personality disorders. Or they have first-degree relatives who have been diagnosed with a psychotic disorder. Patients can be assigned to this subgroup if they have experienced significant reductions in work or study, deterioration in relationships, or overall functionality in their daily lives over the past year.

Comorbid abuse of psychoactive substances in the prodromal stage of schizophrenia

Among the prodromal phenomena, which are often observed on the eve of the onset of schizophrenia, schizotypal and schizoaffective disorders or precede the onset of another attack of schizophrenia, there is the comorbid use of psychoactive substances. This is especially dangerous in children and adolescents, when any environmental stressors that interact with changes in the brain and its functioning act as risk factors for mental disorders [9]. Some patients with schizophrenia with comorbid long-term psychoactive drugs abuse, according to modern epidemiological studies, ranges from 10% to 70% [10,11], and in recent years there has been observed an upward trend of this percentage [12-15]. Among the group of patients with schizophrenia who have a comorbid syndrome of addiction to surfactants, the largest number have a nicotine addiction syndrome (70%) and alcohol (up to 50%) [16]. The use of cannabinoids is considered by some authors in general to be a stress factor that provokes disease recurrence [17]. In general, productive symptoms of schizophrenia are much more pronounced in patients who abuse psychoactive substances, in particular, auditory hallucinations and delusions are more common among people who abuse alcohol [16].

One of the most popular hypotheses for the development of the comorbid syndrome of psychoactive substances addiction is the "self-medication hypothesis" [11], which is used by patients they say to combat the negative symptoms of schizophrenia and to reduce the side effects of neuroleptics [18]. At the same time, with regard to modern science it is possible to assume that in fact there are general neurobiological changes and anomalies, which are likely to be closely related to the syndrome of addiction and mental disorders. Schizophrenia is currently thought to affect the neural circuitry, increasing vulnerability to addiction, with schizophrenia-related abnormalities in the hippocampus and frontal cortex reducing a use of the psychoactive substances control, and a number of neurotransmitters of glutamatergic and dopaminergic systems involved in the development both in the occurrence of psychotic disorders and in the development of addiction syndrome [19].

In relation to the self-medication hypothesis, there is an evidence that nicotine may reduce cognitive deficits and amnestic disorders caused by haloperidol [18], although other studies suggest that patients who abuse smoking usually need to be prescribed significantly higher doses of antipsychotics, due to nicotine-induced acceleration of neuroleptic metabolism [20].

For the recent years, the greatest attention has been paid to studying the effects of cannabinoids on the occurrence and development of recurrences of endogenous psychotic disorders. It is associated both with the prevalence of using these psychoactive substances among this group of patients and the overall increase in cannabis users to 4% of universal population [21]. Indeed, there is an evidence that cannabinoids may act as a risk factor for schizophrenia and other psychotic disorders [22-24]. And cannabis use in adolescence is associated with an increased risk of schizophrenia and schizotypal disorder in adulthood, as well as a decreasing age of onset [25,26].

The main psychoactive compound of cannabinoids is trans-Δ-9 tetrahydrocannabinol (in cannabis indica - Δ-9 Tetrahydrocannabivarin), intravenous administration of which as a pure compound leads to the emergence of transient behavioral and cognitive disorders in healthy people, which resemble some manifestations of endogenous psychoses [25,27]. However, many other cannabinoids may play an important role in the psychopathological modulation of the effects of trans-Δ-9 Tetrahydrocannabinol (THC) [28].

The effect of cannabinoids on the central nervous system is implemented through a system of prejunctional endocannabinoid receptors, among which there are two types:

  1. Cannabinoid receptors of the first type (CB1R), which are responsible for antinociceptive action, cognitive and memory impairment, and are located in the olfactory bulb, cerebral cortex (mainly in the frontal areas), substantia nigra, hypothalamus, hippocampus, striatum and cerebellum, and also, to a lesser extent, in postynaptic membranes, heart muscle, blood vessels, gonads, skeletal muscle, bones and skin [29]. These receptors are associated with the class of G-inhibitors of adenilate cyclase and reduce the release of neurotransmitters and reduce the activity of mitogen-activated protein kinase (MAPK) signaling pathways.
  2. Cannabinoid receptors of the second type (CB1R) are found mainly in macrophages, other cells of the immune system, in hematopoietic cells, in cells of peripheral tissues of the liver, in the endocrine part of the pancreas, in bones and microglia. They are responsible for the release of cytokines.

These receptors are physiologically adapted to interact with two endogenous cannabinoids produced in the human body - anandamide and 2-arachidonoyl glycerol. Recent studies have shown that the level of anandamide in the cerebrospinal fluid of patients with schizophrenia is significantly elevated [30], and in those who used cannabis sporadically, the level of this neurotransmitter was much higher than in those who used cannabis regularly or did not use it at all [31]. The authors of these studies conclude that the level of anandamide is negatively correlated with the severity of psychotic symptoms. The systematic use of cannabis affects the level of anandamide in patients with schizophrenia, but not in healthy users.

At present, we can talk about three scientific models of the possible association of schizophrenia and cannabis use [29,32].

The first model is the "self-medication hypothesis" (the occurrence of a psychotic episode in patients with schizophrenia increases the urge to use cannabis). Scientific data in this case are extremely contradictory, because there are works in which they indicate its confirmation [33-35], while in other research results completely contradict it [36,37].

The second model is the "causal model" (cannabis use leads to a psychotic episode). This model has been the most popular in recent decades. However, there is no specific evidence that cannabis abuse leads to schizophrenia. And although the temporal relationship between cannabis abuse and the subsequent onset of the psychotic state of the schizophrenic spectrum has been well studied and described [38-41], it is not necessary to conclude that cannabis caused schizophrenia. Another argument against this model is the fact that despite the steady increase in the number of cannabis users worldwide, the incidence of schizophrenia remains stable [42].

The third model is the "common factor hypothesis" (there is a common factor that is responsible for the occurrence of psychosis and the development of the syndrome of psychoactive substances use addiction). This model seems the most logical, because, indeed, the increased risk of cannabis addiction and the increased risk of schizophrenia and other psychotic disorders of the schizophrenic spectrum may be associated with some common factor, which may be some genetic or social factors. Predisposition to psychotic disorders and cannabis use may have a synergistic effect on the development of clinically delineated schizophrenia in a group of people affected by this factor [43-45].

It is known that the etiology of schizophrenia is multifactorial and this disease is not the result of genetic factors alone. Some studies have shown that patients with comorbid first episodes of schizophrenia preceded by cannabis use had a personal history of both physical and sexual abuse [46,47]. In addition, comorbid use of psychoactive compounds such as lysergindiethylamide, amphetamine, MDMA, etc. has been studied from the point of view that cannabis is a "gateway to heavy drugs". But data from these groups of patients are also very contradictory. Because some studies suggest confirmation of "common factor hypotheses", while others, on the contrary, contradict it [47,48].

The issue of providing specialized care to patients at the prodromal stage of schizophrenia

The issue of treatment of patients with prodromal stage of schizophrenia, when the clinical diagnosis of the disease has not been established yet, remains extremely relevant and controversial for the present time. The key dilemma in the organization of care for patients who show signs and symptoms of prodrome schizophrenia is the question: should we keep to further follow-up or to start treatment?

International guidelines for clinical practice recommend several practical steps in monitoring patients in a prepsychotic state. But they treat with a caution to use of antipsychotics if the patient does not meet the diagnostic criteria for a psychotic disorder. Therefore, for a patient in the prodromal period of psychosis it is recommended to:

  1. Involve the person in the risk group;
  2. Assess and monitor mental state;
  3. Provide support and treat comorbid conditions;
  4. Conduct psychoeducation for the patients and their families;
  5. Promote the development of the patient's skills to master psychotic symptoms;
  6. Avoid stigmatization, prevent self-stigmatization of the patient;
  7. Avoid prescribing antipsychotics until the criteria for psychotic disorder according to ICD 10 or DSM 5 are present.

Some data support the feasibility of cognitive-behavioral therapy (CBT) during the initial prodromal phase and the addition of an atypical low-dose antipsychotic if the patient progresses to a later stage characterized by BLIPS or APS. But the same research emphasizes that a combination of CBT and antipsychotic medications can only delay but not prevent the progression of a mental disorder. Any risk of adverse metabolic complications precludes the use of atypical antipsychotic medications. One possible alternative is to use omega-3 polyunsaturated fatty acids.

It would be a clinically useful approach to consider prodromal schizophrenia not as a separate diagnostic category for DSM 5, but as a set of signs and symptoms associated with an increased risk of developing psychosis. Accordingly, individuals in this phase require close monitoring and possibly early initiation of an antipsychotic. It is important to involve the patients and their families at an early stage to teach them to navigate the diagnostic uncertainty, to help them deal with stigma, to manage risk factors and, finally, to jointly define an intervention strategy.

The Cochrane Systematic Review Database contains a protocol for a meta-analysis of early interventions in the prodrome stage [49], which must be conducted over a 20-year period using clinical criteria to identify people at risk for schizophrenia, including high-risk clinical criteria (HRC) (at-risk mental state (ARMS) or "prodromal syndrome"); ultra-high-risk criteria (UHRC) (attenuated psychotic syndrome (APS), Brief Limited Intermittent Psychotic Syndrome (BLIPS), and "genetic risk combined with dysfunction".

The following interventions will be taken into account:

  1. Pharmacotherapy: any oral antipsychotic medications.
  2. Alternative medications (e.g., omega 3, vitamins B12, B6, folic acid).
  3. Psychotherapy: including psychodynamically oriented individual psychotherapy, cognitive behavioral psychotherapy, group therapy (psychodynamically oriented), systemic therapy, interpersonal therapy, integrative therapy, family therapy.
  4. Psychosocial interventions: including psychoeducation (individual, group and family), metacognitive training (individual and group), cognitive rehabilitation training, social skills training.
  5. Combined pharmacotherapy and psychotherapy or psychosocial interventions; or psychosocial interventions involving a combination of at least two approaches, one of which is pharmacotherapy and another one psychotherapy or psychosocial intervention.
  6. Placebo.
  7. No intervention (short consultations on outpatient basis are allowed less than once every 3 months).

As preliminary conclusion, the authors identified three groups of interventions and noted their features:

  1. Pharmacotherapeutic treatment, including antipsychotics, thymostabilizers and antidepressants. Antipsychotic therapy is a well-established treatment for the first episode of psychosis. However, due to a number of potential side effects and the lack of reliable evidence that it is effective in preventing psychosis, antipsychotic treatment is currently offered in the prodromal phase of the disease only for more complex cases and only for a few atypical antipsychotics [50]. Antidepressant treatment is not recommended for the treatment of an episode of the acute psychosis, as evidence suggests that antidepressants may be associated with a risk of worsening psychosis. However, it is suggested that the treatment of prodromal-depressive syndromes may actually delay the onset of psychosis [51,52]. Thymostabilizers are used to treat first- or second-line bipolar disorder, but their use in the prodromal stage may be useful [53]. Anxiolytics are used to briefly reduce anxiety in the first episode of psychosis. It is believed that the reduction of anxiety in the prodromal phase of the disease may delay psychosis [54].
  2. Use of nutrients / supplements and alternative medications (omega 3, glycine, d-serine, B vitamins, folic acid, modulators of the immune response). Based on the hypothesis of changes in lipid metabolism, homocysteine levels and neuroinflammation in schizophrenia, a number of studies have studied the effects of various supplements aimed at restoring lipid metabolism or low vitamin content in people at high risk of psychosis, where in some cases their effectiveness was proven [55,56].
  3. Psychotherapy or psychosocial interventions, including psychoeducation, social skills training, metacognitive learning, cognitive recovery, family therapy, individual psychotherapy, combined integrated approach. Most studies focus on psychosocial methods of varying duration and offer psychosocial interventions as the first-line therapy for the prodromal stage. Studies have shown variable and generally low effectiveness of various psychosocial methods for people with schizophrenia, especially during a longer evaluation period [57-59]. Cognitive-behavioral therapy has been shown to be the most effective in several randomized controlled trials.

Indeed, today there are many treatment options in the prodromal stage of schizophrenia, and each of them may be effective due to the peculiarities of the impact on the brain of patients. Thus, pharmacotherapy with antipsychotics is effective against psychotic symptoms due to their blockade / agonism of multireceptor areas of the brain. In particular, cortical transmission of dopamine via D1-receptors may play a role in impaired working memory and negative symptoms, while dopamine activity in the striatum via D2-receptors may modulate response inhibition, temporal organization, and motor performance [60].

Thymostabilizers can act as modulators of neurotransmission of glutamate, counteracting the effect of excessive transmission of glutamate. Anxiolytics may increase GABA neurotransmission, subsequently reducing excessive glutamate transmission. Both support the glutamate hypothesis of schizophrenia. Antidepressants may increase serotonergic, noradrenergic or dopaminergic neurotransmission in the prefrontal cortex, subsequently affecting cognitive and depressive symptoms in the prodromal stage of schizophrenia.

Nutrients / supplements and alternative medicines (omega 3, glycine, d-serine, B vitamins, folic acid) act as glutamatergic modulators (glycine, d-serine), suppressing the increased immune response (acetylsalicylate and others) or counteracting the altered phospholipid metabolism observed in some people with schizophrenia [45,46].

Psychosocial interventions can increase self-confidence and self-esteem, cognitive abilities, social skills, social interactions and social support, all of which help to overcome coping mechanisms and reduce anxiety and vulnerability to stressors and subsequent psychosis. The low risk associated with the use of omega-3 fatty acids and psychosocial interventions suggests their benefits as a method of preventive intervention for people who are likely to prodromate. Most researchers are in favor of the combined treatment of prodrome with a combination of antipsychotic and / or antidepressant medications, psychotherapy for the patients and their families, as well as omega-3 fatty acids.

Conclusion

Although the prodromal stage of schizophrenia is potentially the most optimal target for primary medical intervention, the issues of clinical verification of this condition and methods of therapeutic intervention require further research and confirmation of results in real clinical practice. In addition, a number of legal issues remain unresolved, because the provision of specialized medical care to persons who have not been diagnosed with a mental disorder is currently in a certain legal vacuum.

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How to Cite

1.
Khaustova О, Omelianovych В. Modern approaches to the diagnosis and care of patients at the prodromal stage of schizophrenia. PMGP [Internet]. 2020 Feb. 17 [cited 2024 Mar. 19];5(1):e0501232. Available from: https://dev-ojs.e-medjournal.com/index.php/psp/article/view/232