The role of genetics in the vulnerability to psychosis and in predicting clinical outcome. Data from the Psychosis Incident Cohort Outcome Study (PICOS)

While the evidence for a genetic contribution to schizophrenia and bipolar disorder is strong, the genetics is complex with environmental factors contributing as well. The inconsistent results and disappointing findings of genetic research into functional psychosis may be due to the intrinsic characteristics of the phenotypes under investigation: the “diagnosis of schizophrenia” and the “diagnosis of bipolar disorder”. Although the DSM/ICD definition of schizophrenia/bipolar disorder has an undoubtedly high clinical utility, it does not provide information about the fundamental nature of the illness. For example, the manifest clinical heterogeneity of schizophrenia, combined with a failure, to date, to demonstrate the existence of a unitary disease process, has led to the conceptualization of schizophrenia as a heterogeneous disorder. Consequently, to obtain a correct classification of psychosis, it is important to understand whether the heterogeneous group of syndromes placed under schizophrenia specific diagnosis is one, or many, diseases. To achieve this aim, the relationship between phenotype and genotype pattern should be ascertained, to detect whether specific variation in a gene imparts risk for a specific form of the illness. One approach to resolve this controversy is to examine the relationship between the clinical features of illness and genetic factors, in addition to selecting cases on the basis of a specific ICD-10 or DSM IV diagnosis of schizophrenia or bipolar alone. The present study aims, in a cohort of first episode psychosis, to study whether genetic variants are associated with functional psychosis and with one endophenotype (Neurological Soft Signs). Moreover it will be studied whether genetic polymorphisms can determine the clinical profile of psychosis at the onset of the illness. The present research was conducted within the broader framework of the PICOS study. The PICOS (Psychosis Incident Cohort Outcome Study) is one of the most comprehensive and largest multisite collaborative research projects ever done in Italy. It was performed in Veneto Region: among the Departments of Mental Health the vast majority has accepted to participate in the study, covering 81.4% of the total regional population (about 3.685.000 inhabitants). A representative cohort of subjects presenting with psychotic symptoms from January 1st 2005 till December 31st 2008 to Community Mental Health Services in the participating catchment areas has been characterized at baseline and then followed-up for 1 year: a comprehensive set of biological, environmental, demographic, clinical and neuropsychological variables were collected by interviewing both the individuals themselves and their carers. Patients were assessed with a set of standardized measures which include: Schedule for Clinical Assessment in Neuropsychiatry (SCAN), Scale for the Assessment of Positive and Negative Symptoms (PANSS), Bech-Rafaelsen Mania Rating Scale (BRMRS), Hamilton Rating Scale for Depression (HAM-D), Global Assessment of Functioning Scale (GAF), Premorbid Adjustment Scale (PAS); Test d’Intelligenza Breve (TIB, Sartori et al, 1997), the Italian version of the New Adult Reading Test (NART), Neurological Evaluation Scale (NES); Family Interview For Genetic Studies (FIGS). For each subject, venous blood samples (15 ml) were collected in EDTA-containing tubes and DNA was extracted. Several SNPs in DTNBP1, NRG1, DISC1, COMT, DAOA/G30, BDNF, DRD2, DRD3, MAOA genes were genotyped. In the context of PICOS, 351 patients, with a diagnosis of schizophrenia (24%), non affective (55%), and affective psychoses (21%) were assessed at baseline. Within this group, 213 patients gave their DNAs for the genetic analysis. In addition, 514 controls selected from a population similar to the patients with regard to ethnicity and area of residence were recruited from the Blood Transfusion Service in Verona and were genotyped. In the PICOS sample, it was found that some haplotypes in DISC1, NRG1 and DAOA occurred more often in cases compared to controls than expected by chance. Sixty-two subjects with a first-episode psychosis underwent the NSS evaluation. It was found that there is a relationship between having “high” NSS in “sensory” and “sequencing” neurological dysfunction scale and the severity of psychopathology and the negative dimensions. Moreover, patients with “high” NSS in the total score of NES have greater score in the negative dimension and in the total score of the PANSS. The PICOS study indicates that the NSS are not artefacts or epiphenomena of the severity of the illness and that they are present at the very onset of psychosis. Due to the fact that it remains inconclusive whether NSS could be a trait or state marker, or both, for schizophrenia, longitudinal studies are required to confirm the stability of NSS over the course of illness. In conclusion, the difficulties in gaining a consistent and clear-cut picture of the genetics of schizophrenia and bipolar disorder mirror the marked clinical and neurobiological heterogeneity of the disorder. A comprehensive global model to understand clinical heterogeneity in schizophrenia is still lacking. It will be necessary in the future to conduct studies that define persistent aspects of the psychotic profile which are more likely to represent an underlying biological pathogenesis as opposed to fluctuating, possibly environmentally mediated symptoms.