Schizophrenia. The new look at the way of treatment.

НИИ клинической иммунологии СО РАМН,
Кафедра психиатрии ФУП, ГБУЗ НСО ГНОПБ №5. г. Новосибирск.
Воронов А.И. Дресвянников В.Л. Пухкало К.В.

Recently, during one of the experiment was found new effective way of treatment schizophrenia. The current treatment is based on convenient, noninvasive way of transporting cytokines exactly towards the area of mesolimbic circuit. The data collection result of this particular study proved the existence of autoimmune theory of schizophrenia.

To begin with, all patients suffering from schizophrenia disease have increased dopaminergic activity in the mesolimbic pathway and decreased dopaminergic activity in mesocortical. Therefore, modern treatment is based on the usage of antipsychotic drugs that can suppress dopamine and serotonin activity. In comparison with pschycotic symptoms, negative symptoms barely can be treatable under this type of therapy. Dementia praecox – is an inevitable outcome of a particular schizophrenia. According to Robert Whitaker study (Boston Global Article series, 1998) has shown that antipsychotic drugs temporarily deaden psychosis. However, after prolonged usage of antipsychotic drugs patients become more biologically prone to psychosis. It is also important to point out that the usage of psychotropic drugs in order to deaden schizophrenia symptoms lead to a deterioration of one of the immunological parameters, greater decrease in the proportion of T - cells in peripheral blood of these patients (2). According to positive and negative syndrome scale (PANSS) the neuroleptic drugs treatment gives the optimal 60% percent of clinical improvement. Under this treatment of schizophrenia, after four months the percentage equals 10 % and after 12 months the percentage increases until 20% cases. Unfortunately, neuroleptic drugs, even the most modern ones do not have a capacity to treat schizophrenia symptoms properly. As an example I would like to introduce the description of one clinical case.

The patient X, female, 19 years old had two main episodes of schizophrenia symptoms. First symptoms appeared when patient X was 17 years old. Before schizophrenia symptoms occurred, patient X was an active, friendly, skilled high school student. Suddenly, in the period of Christmas holidays, without any reasons, patient X started to suffer from the lack of energy, unreasonable and unexplainable fear and completely shrank in herself. Right after Christmas holidays were over, patient X refused to go to school and continue her education. By that time, she also was suffering from insomnia and as a result did not sleep at all around two weeks. According to her family, patient X was lying in bed whole nights in a row with wide open eyes, shaking from any noise. During this period patient X had an appointment with several neurologists and psychotherapists, who prescribed her Grandaxin and Glutethimide along with high physical activity. However, patient X kept complaining on insomnia and fatigue. Food preferences also had change since first symptoms had appeared. As an example, patient X could not feel the taste of meal and especially her favorite food. According to patient X, the fish, that she used to like a lot, now emits an awful odor; patient X smells this odor all the time even when there is no fish nearby. Also, patient X started to complain on the “man’s voice” that forces her to hang herself. In summation, in this particular case we should mention that patient X has genetic susceptibility. One of her close relative was suffering from the same symptoms and was diagnosed with schizophrenia decease.

After psychotherapist’s appointment, patient X was diagnosed with schizophrenia decease and as a result was admitted to the mental hospital. In accordance with patient’s X and her relatives’ agreement, patient X became a participant of the experiment treatment of schizophrenia. The main condition of the current treatment is the rejection of traditional antidepressants, tranquilizers, and neuroleptic drugs. Instead of traditional drugs patient X was prescribed experimental cryopreserved composite liquid of cytokines (ССSC). Every 8 hours this liquid had to be taken through the steam nose inhalation (10ml per dose). An hour after the second dose of medicine, patient X started to feel better and explained that the unreasonable fear and voices that she heard previously disappeared. After the third dose of medication, patient X was able first time within last two weeks to fall asleep. The duration of her sleep was 9 hours and can be described as a normal.

The patient X was observed within next 48 hours and her behavior had no schizophrenia symptoms. Food preferences recovered and healthy appetite appeared. The experimental treatment was over. Without any addition prescription patient X was able to sleep every night around 6 hours per night. Three days later patient X being completely healthy (no decease symptoms) was sent home. However, the first night at home patient X was barely sleeping (only two hours) and had hallucinations. Later, patient X mentioned that she saw two huge eyes staring at her from the darkness. The next morning after this case she was returned back to the hospital, where experimental treatment was renewed and scheduled. Since that time, patient X had to take inhalation every morning within next 5 days. During the experimental treatment schizophrenia symptoms disappeared and patient X was able to talk about the hallucinations she had. Patient X even mentioned that all the hallucinations probably were just dreams. Since second effort of experimental treatment patient X was able to eat and sleep every night (around 6 hours per night). After one week of observation, with a portable nebulizer patient X was transferred to outpatient treatment. However, experimental treatment with every morning inhalations was continued within next two months. The dosage of cryopreserved composite liquid of cytokines (ССSC) was the same 10 ml. Within February and March patient X was able to sleep every night around 4-6 hours, then the amount of hours increased till 8 hours per night. However, according to her family, patient’s X behavior in that period of time could not be described as independent and completely healthy. Also, patient X was complaining that she was not able to memories any information she read. The experimental treatment was continued within the whole April and in the beginning of May patient X started to attend school again. The experimental treatment that consisted of 108 cytokines inhalations was finally stopped. During the whole experiment neuroleptic drugs, antidepressants and tranquilizers were not applied. According to the observation and the conclusion of experienced psychiatrists within the next year patient X had no schizophrenia symptoms. Thus we should point out that according to PANSS scale patient X had 100% remission.

Second episode of schizophrenia symptoms was happened after the prolonged remission. A year after, exactly during the winter time patient X started to suffer from insomnia, along with auditory and visual hallucinations. Patient X stopped eating, left school and in acute psychotic state was hospitalized in a psychiatric clinic, where spent next month and a half. According to medical history patient X was taken high dosage of such kind of drugs as Haloperidol, Clopixol, Aminazine and Cyclodol. Despite all the efforts to suppress and treat symptoms of the current decease, patient X developed neuroleptic syndrome, complicated by fecal impaction. During the whole treatment, patient X kept suffering from hallucinations. Sometimes hospital personnel had to type patient X to bed. Because of non-effective treatment, month and a half later patient’s relative signed the agreement to participate in experimental treatment again, that was applied one year ago and had a positive results. Before the experimental treatment was renewed patient X was observed by the committee of experienced psychiatrists, who reported that patient X is suffering from acute paranoid schizophrenia decease complicated by hallucinations.

The first step of experimental treatment was to cancel all previously taken drugs. Cytokines inhalation was prescribed every 8 hours within the first 64 hours. During the beginning of treatment patient X kept suffering from hallucinations; her behavior can be described as highly unstable, hyper excited and non-adequate. After 64 hours patient X became quite and was able to sleep again. Hallucinations disappeared. After 5 days of treatment inhalation was prescribed only every 12 hours, patient X started to feel better. However she was complaining on diffuse attention. After 15 days patient X was prescribed to take only one inhalation per day; she was able to sleep and adequate judge her decease symptoms and talk about the hallucinations she had previously. After two month, when patient X was taken inhalation once per 3 days, her emotions and normal behavior recovered. According to PANSS scale we can mention again that we have an example of 100% remission.

In order to focus readers’ attention on the explanations of the way new treatment of schizophrenia works, clinical examples with supporting description was presented at the very beginning of the current article. The rest of the article will introduce to readers detailed interpretation of the experiment.

The autoimmune theory of schizophrenia and some other psychotic deceases is not modern Krasnushkin (1920) & Snesarev (1934). In USA and Soviet Union (Russia) in the late 60s there were successful studies of autoimmune theory of schizophrenia. For example, some researchers were using the immunofluorescence method in order to prove that patients suffering from schizophrenia decease have abnormal immunoglobulin - antibody that reacts with the elements of brain tissue. In 80s in one of the mental clinics in Tomsk (Russia) researchers got sufficient data collection. According to that fact schizophrenia decease activates B-cellular level of humoral immunity as well as specific immune disfunction of T-cellular level (3). The current autoimmune theory encouraged us to make a clinical therapeutic experiment and to use cytokines in order to suppress and treat schizophrenia symptoms. By continuing experimental treatment we are hoping to prove the existence of autoimmune theory. Under the observation of experienced researchers and psychiatrists experimental treatment brought positive results. Some participants of the experiment, who were diagnosed with schizophrenia, had showed 100% remission within the next 5 and 7 years after the treatment. At the very beginning of the experiment, cryopreserved composite liquid of cytokines (ССSC) were injected intravenously. Currently, it was found more efficient way of transportation cytokines directly to the brain. The new way of nasal inhalation of cytokines liquid is based on spraying a concentrated solution of cytokines with a help of a portable nebulizer. This device has a special attachment that helps to transfer cytokines through the olfactory spots of the upper nasal directly into brain. This particular method is highly convenient and suitable for the usage of other autoimmune neurodegenerative diseases treatment.

Arteries that are directly connected (anastomosis) with intracranial vascular provide the blood supply to nasolabial triangle, all the shells and mucous membrane of the nose. Thus, through the slowly nasal inhalation some elements can be easily transported directly into the brain. Cytokines have an ability not enter the brain only through the blood flow but also through axonal transport immediately contact with olfactory neurons. Exactly through the field of olfactory fields and mucous membrane of the nose, human brain contacts with external environment. The olfactory system is the only one system in which the sensory neurons of the brain have direct contact with the outside world. The size of the olfactory spots area can reach ten square centimeters. Extending from the olfactory neurons, long and thin axons project to the olfactory bulb. Neurons give rise to the axons that are ending in synaptic contacts on the cells of the olfactory cortex. The transaction of the sensory signals to the limbic system is direct. The sense of smell functions serves as a recognizer of concentration gradients of the intensity of a wide range of substances, especially dangerous one (4).

According to human anatomy, there is one direct way through which cytokines are able to enter quickly the sub cortical region. Researchers found out, that even small particles of the dust can be transferred to the body through neurons transport system. There are some studies that point out the capacity of microscopic toxic dust can enter the brain through olfactory bulb (5). Micro dosage of cytokines that enter the olfactory mucosa of the nose area leads to the immediate absorption. By penetrating into the arterial blood stream in the immediate vicinity of the anastomosis of supraorbital and intracerebral arteries, cytokines enter through Willis' artery to base of the brain. In other words cytokines reach directly the blood vessels in the limbic system where emotions are anatomically formed. We also should mention that sub mucosal layer of the roof of the nose that is located in the area of olfactory bulb and olfactory spots, contains glial and neural stem and progenitor cells. At a constant natural mortality of receptor neurons caused by direct contact with external environment, regenerating axons of these cells have to recover the lost synaptic connections (5). Permanent neurogenesis in the olfactory system is one of the oldest defense mechanisms. Stem cells are constantly presented in certain areas of the forebrain and the olfactory bulb. Hence, stem cells can migrate to the foci of the autoimmune destruction, turning it into neurons; furthermore assume the functions of lost neurons. It is proved that after a stroke, cerebrocranial injury, brain stem cells can be activated independently and move to the affected area. They are not only able to turn into neurons, glia, and stroma, but also to replace the dead neurons, and possibly embedded in neural ensembles. There were found open areas in the front of the human brain, where lifelong new nerve cells continue to form. In addition, in the forebrain there are always presented glutamatergic nerve cells, which are regularly shared. They can be detected through specific transcription factor Tbr2, which exists only in the progenitor cells of these cells.

The Homing (autonomous migration of immune cells on the gradient of cytokines) of stem cells in the brain were found solely in the mouse model. The stem cells migrate from intact neighboring areas into the damaged brain tissue. There, they form mature neurons by producing a replacement of the damaged nerve cells with new ones. For example, rat’s neuronal stem cells are located near the lateral ventricles of the brain. Their rebirth into the neurons is very intense. In adult rats during one month, the stem cells produce about 250 000 new neurons by replacing the 3% of all neurons in the hippocampus. In rats the life span of these neurons is very high and can reach up to 112 days. The stem neuronal cells have an ability to overcome a long way (about 2cm) for the short period of time. They are also capable to migrate to the olfactory bulb and there turn into the neurons. According to Magdalena Gotz (6), neural precursor cells can form new nerve cells in the adjacent cerebral cortex. Liu Z. (et all) also pointed out that patients with brain cancer are injected with bromodeoksiuridin (BrdU - can serve as a marker) in order to provide the beginning therapy in the pre-terminal stage of the cancer. This substance accumulates in the newly formed cells and can be easily observed. This allows us to trace the path of its migration. Thus was found out that in humans, the core of the olfactory bulb contains its own, constantly proliferating, multipotent stem and progenitor cells, which upon the following culturing turn into neurons and glia. [8].

By applying to our experimental treatment we should point out that cytokines liquid possibly has a significant influence on the immune reaction. The current influence can be described as a movement from Тh2 to Тh1, where through non-invasive way cytokines transfer towards the limbic system and slow down the Th2 process of destruction in the brain. As a result, during the one week all schizophrenia symptoms disappear.

Modern treatments with the stem cells are based on the injection of fetal stem cell into the damaged area or sometimes injection through the peripheral vein. However, the influence of the stem cells after the injection on the human body can not be predictable and all of the following processes can not be monitored. Thus, in 30% of all cases stem cells treatment may lead to the development of cancer decease. The other issue that can be caused by the stem cells treatment is that the neurons that appeared from the stem cells have no ability to adapt to the nerve system. The current issue may occur because of the defense mechanism of the human nerve system. For example, there was found some specific signaling substances that appear in the area of injury and prevent the formation of intercellular contacts. In comparison with other tissues in the human body, nerves tissue is the one that can not be replaceable; every neuron has unique information. Furthermore, neurons are also active elements of the control system. Thus the replacement of natural neurons by the neurons that were produced with the help of the stem cells may lead to uncontrollable changes in the human body.

In the current experimental treatment through the special combination of cytokines we activate natural stem cells and force them to leave cellular level. This is a fundamentally new therapy with the usage of the stem cells. Under the homing law stem cell automatically move towards the damaged area in order to fix the problem (5). According to the reduction of schizophrenia symptoms during our experimental treatment the stimulated by cytokines stem cells replace damaged neurons and take their function.

During the last 10 months one more patient with diagnosis schizophrenia was under the experimental treatment. The 27 years old patient was suffering from the disease within last 6 years, which led to obvious defect and brain damage (verbigeration, autism, intellectual mnestic reduction, emotional flattening). By the current time, under the experimental treatment the progressive process of the development of the disease was stopped. Furthermore, we should mention that after cytokines inhalation the damaged area reduced. The percentage of the progress under the current experimental treatment according to PANSS scale is above 70%.

Schizophrenia is an organic brain damage that can be caused by the genetically determined vulnerability of the blood-brain barrier. The latter one leads to the autoimmune destruction of the nuclei and glial mesolimbic circuit. The progression of the disease can be described through the localization, power and high speed of the development of autoimmune reaction. Autoimmune process is initiated, guided and supported by the natural groups of cytokines. In order to stop autoimmune process we should use internal sources of the body, which in this case can serve cytokines. Their proper selection of the cytokines allows to stop, to modify or to slow down the destructive autoimmune process. The earlier the destructive process will be stopped - the greater part of the human brain will be saved. Thus the current experimental treatment is not only successful but also pathogenetic.

Ilya Ilyich Mechnikov wrote, "I know very well that many of my ideas and works are hypothetical, but the positive results can be reached only with the help of hypotheses; thus without any doubts I was publishing all my ideas. I believe that younger generation will thoroughly test and develop them”.

References:

1. Vartanajn M. E. et all (1987), A psychiatrist's point of view on the immune modulation: neuro-immune interactions and its mechanisms.

2. Vetlugina T. P. (2003), Clinical Psycho neuro immunology.

3. Nauta U. et all (1982), Brain structure, Moscow - Mir

4. Retrieved from www.moikompas.ru/compas/neuron_progenitor

5. Retrieved from www.medlinks.ru

6. Liu Zh., Martin L.J. (2003), Olfactory bulb core is a rich source of neural progenitor and stem cells in adult rodent and human. J.Comp. Neurol; doi: 458:368-391.

7. Retrieved from www.gerontology-explorer.narod.ru