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ERANET NEURON Project: Linking synaptic dysfunction to disease mechanisms in schizophrenia - a multi-level investigation (SYNSCHIZ)SCIENTIFIC REPORT - PHASE 1PHASE 1 NAME: Complex characterization (clinical, electrophysiological, imagistic) of a first group of patients with schizophreniaAbstarctSchizophrenia (SZ) is a severe psychiatric disorder characterized by a wide range of cognitive impairment and a complex set of symptoms including hallucinations, delusions, thought and affective disorders. SZ is one of the major challenges for society with serious repercussions for both patients and the caregivers. Currently, a cohort of 200 patients with schizophrenia including 193 adult patients and 7 adolescents, has been established. All patients have been clinically and paraclinically evaluated by biological tests and electrophysiological studies (EEG); blood was drawn for the extraction of DNA from 39 patients, for further genetic studies. INTRODUCTION Schizophrenia (from the Greek: schizein = split, splinter, phren = mind, soul) is a mental disease included in the category of endogenous psychoses. It is characterized by the appearance of some major psychopathological manifestations, such as hallucinations, delusions, thought disorders, affective disorders, behavioral disorders, disorganization of personality. Up to now, no detectable organic causes have been revealed. For the diagnosis of schizophrenia a minimum duration of morbid manifestations of at least one month (ICD 11) or at least 6 months (DSM V) is mandatory. Schizophrenia is one of the most severe psychiatric conditions with serious repercussions for both patients and the caregivers. Despite the modern treatments that radically changed the prognosis of the disease and the social inclusion of the patients, often the evolution of the disease is hard to be predicted.The frequency of schizophrenia is 0.5-1%, with an annual incidence rate of 0.05%. The probability of a person getting sick of schizophrenia during his or her life is on average approx. 1%. More than half of the illnesses occur between puberty and the age of 30. Under the term "late schizophrenia" are included cases with an onset after the age of 40 years.Schizophrenia has no single cause; its occurrence is due to the interaction of several biological, psychological and cultural factors with predisposing genetic vulnerability.Signs and SymptomsThe symptoms of schizophrenia fall into three categories: positive, negative, and cognitive.Positive symptoms: “Positive” symptoms are psychotic behaviors not generally seen in healthy people. People with positive symptoms may “lose touch” with some aspects of reality. Symptoms include:HallucinationsDelusionsThought disorders (unusual or dysfunctional ways of thinking)Movement disorders (agitated body movements)Negative symptoms: “Negative” symptoms are associated with disruptions to normal emotions and behaviors. Symptoms include:“Flat affect” (reduced expression of emotions via facial expression or voice tone)Reduced feelings of pleasure in everyday lifeDifficulty beginning and sustaining activitiesReduced speakingCognitive symptoms: For some patients, the cognitive symptoms of schizophrenia are subtle, but for others, they are more severe and patients may notice changes in their memory or other aspects of thinking. Symptoms include:Poor “executive functioning” Trouble focusing or paying attentionProblems with “working memory” Schizophrenia in children and adolescentsSchizophrenia diagnosed in a child or adolescent has the same DSM definition as an adult and is characterized by the presence of positive and negative symptoms. The presence of these symptoms is associated with an important deterioration in social functioning.A diagnosis of infantile schizophrenia can be establish only in children with a previous normal or apparently normal neuropsychiatric development; there are some children with pervasive developmental disorder with a particular evolution towards schizophrenia.Usually, schizophrenia in children has a more severe phenotype and more important genetic influences.Diagnostic problemsA typical clinical expression of schizophrenia according to ICD or DSM criteria is found only in adolescents, very rare in children.Schizophrenia with childhood onset has some particularities:? Insidious onset;? premorbid functioning including: social isolation, multiple delays in development - in motor, coordination, sensory, cognitive, and social areas; bizarre preoccupations;? Delirium is less complex, with themes that reflect children's preoccupations? Children's perceptual disorders may have as source: imaginative themes, fantastic interpretation of intrapsychic experiences, confabulatory and oniric phenomena, dissociative phenomena, factitious symptoms? Formal thinking disorders such as loss of associations and illogical thinking may also be present. In children, we must take into account of the mechanisms of imaginative and fantasy games that are specific for this age.OBJECTIVEThe objective of the first phase of the project was the initiation of the patients group.METHODS A. Elaboration of the documents for obtaining the approval from Ethics Committee of the Clinical Hospital Of Psychiatry "Prof. Dr. Alex. Obregia".Specific documents, which included informed consent to the patient or his / her legal representative and a description of the project, were submitted to the Ethics Commission of the Clinical Psychiatric Hospital "Prof. Dr. Alex. Obregia ". The Ethics Commission approved the project activities.B. Methodology for clinical evaluation of patients with schizophreniaA working protocol was developed for constitution of the patient group.PROTOCOLVisit 1The patient corresponds to the inclusion criterion and does not corresponds to the exclusion criterion.Inclusion criterion: diagnosis of schizophrenia including all the subtypes according with the DSM IV TR and ICD 10. Exclusion criterion: psychoactive substance use that can induce psychosis.The patient / legal representative is informed about the present study.The patient / legal representative signs the Informed Consent in 2 copies in the presence of the doctor and keeps a copy.DemographicsPatient code SexDate of birthEthnicityClinical evaluation including: blood pressure, pulse rate, weight, height, body mass index, waist, cranial perimeterDiagnosis: Schizophrenia with all the subtypes according to DSM IV TR and ICD 10Blood taking Complete blood countHormones: TSH, fT4, prolactinInflammation markers: ESR, CRPBiochemistry: TGP, TGP, GGT, LDL-cholesterol, HDL-cholesterol, triglycerides, total lipids, glycaemia, HbA1cIonogram: Na, K, ClBlood for DNA extractionPatient historyFamily historyPersonal medical history – comorbidities (medical documents to prove) with associated medicationPsychiatric history - data on the age at onset, number of episodes, the degree of remission of inter-episodes symptomatology, the previous neuroleptic treatment, the mentioning of possible suicide attemptsScales: PANSS, Calgary Scale, Sheehan Disability Scale (SDS), Addenbrooke’s Cognitive ExaminationSetting up a schedule for EEG, MRIThe patient / legal representative is invited to return to a later (optional) visit to discuss the outcome of medical investigations.C. Methodologies for electroencephalogram (EEG) recording EEG studies were performed using a 32-channel electroencephalograph according to the standard protocol:- Wake-up recording with closed eyes and open eyes - 5 min .;- Hyperventilation stimulation - 5 minutes;- Intermittent Photic Stimulation D. Biological samples processingBiological samples from patients enrolled in the study were processed and preserved for subsequent molecular investigations. The peripheral blood samples for genetic testing were collected on EDTA tubes. The first processing step consisted of isolating the nucleated cells from whole blood. A protocol based on red cell lysis with a buffer containing ammonium chloride (NH4Cl), sodium bicarbonate (NaHCO3) and EDTA was used. Briefly, the blood samples were treated twice with the red cell lysis buffer and subsequently washed twice with 1X PBS solution. The white cells pellet was resuspended in ~ 200 μl 1X PBS solution and stored at - 800C. A protocol for genomic DNA extraction for subsequent molecular investigations was established in order to standardize the procedures for gDNA isolation, quality control and storage.RESULTS In the current stage, 200 patients with schizophrenia were clinically evaluated: 193 were adult patients with paranoid schizophrenia and 7 were adolescents with repeated psychotic episodes. The anamnesis included:- history of the disease: onset of symptoms, evolution, trigger factors;- family history: the existence of other relatives with schizophrenia or other mental illness in the patient's family;- personal history: school and professional route, alcohol, tobacco or drugs consumption, association of other medical conditions.Diagnosis of schizophrenia was established based on DSM IV / ICD-10 criteria.It should be noted that three of the adolescent patients included in the study had a family history of schizophrenia or other psychiatric illnesses, namely: - a 14-year-old girl – her mother is placed in a psychiatric hospital with a diagnosis of schizophrenia; - a 16-year-old boy with several family members with psychiatric disorders: the patient's mother, 38 years old, was diagnosed with schizophrenia with onset in high school, the uncle died of suicide at the age of 35, the paternal grandmother's sister is diagnosed with depressive disorder, and a paternal uncle, 35-year-old is diagnosed with bipolar disorder. - a 16-year-old girl – has 2 siblings with intellectual disability, her mother has, also, intellectual disability.No other significant pathologies have been noted.All patients were evaluated by biological tests. No significant anomalies of these tests were noted. Electrophysiological studies have also been performed in all patients, which have revealed an alpha frequency reduction and an increased fast activity in most patients.Nuclear Magnetic Resonance (MRI) studies were performed in 2 patients, without any pathological aspects.Blood samples from 39 patients enrolled in the study were processed and preserved for subsequent molecular investigations.In order to disseminate information about the project, we presented two communications:Magdalena Budisteanu, Sorina Mihaela Papuc, Dan Riga? Sorin Riga, Aurora Arghir. A multidisciplinary approach of patients with schizophrenia – from deep phenotyping to genotyping and back. Scientific Session of “Victor Babes” National Institute of Pathology. Bucharest. Nov. 2018Magdalena Budisteanu, Sorina Mihaela Papuc, Dan Riga? Sorin Riga, Aurora Arghir. Genetic mechanisms of schizophrenia – presentation of ERA-NET NEURONproject SYNSCHIZ. National Congress of Romanian Society of Medical Genetics. Gura Humorului. Sept. 2018.CONCLUSIONS? A first group of 200 patients, including 193 adult patients and 7 adolescents, was established.? The patients’ data, including anamnesis, clinical evaluation and paraclinical studies, were recorded in the patients’ files. ? Blood samples from 39 patients enrolled in the study were processed and preserved for subsequent molecular investigations. ................
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