BACKGROUND: The aim of the current study was to explore the changing interrelationships among clinical variables through the stages of schizophrenia in order to assemble a comprehensive and meaningful disease model. METHODS: Twenty-nine centers from 25 countries participated and included 2358 patients aged 37.21 ± 11.87 years with schizophrenia. Multiple linear regression analysis and visual inspection of plots were performed. RESULTS: The results suggest that with progression stages, there are changing correlations among Positive and Negative Syndrome Scale factors at each stage and each factor correlates with all the others in that particular stage, in which this factor is dominant. This internal structure further supports the validity of an already proposed four stages model, with positive symptoms dominating the first stage, excitement/hostility the second, depression the third, and neurocognitive decline the last stage. CONCLUSIONS: The current study investigated the mental organization and functioning in patients with schizophrenia in relation to different stages of illness progression. It revealed two distinct "cores" of schizophrenia, the "Positive" and the "Negative," while neurocognitive decline escalates during the later stages. Future research should focus on the therapeutic implications of such a model. Stopping the progress of the illness could demand to stop the succession of stages. This could be achieved not only by both halting the triggering effect of positive and negative symptoms, but also by stopping the sensitization effect on the neural pathways responsible for the development of hostility, excitement, anxiety, and depression as well as the deleterious effect on neural networks responsible for neurocognition.

1st Department of Psychiatry Faculty of Medicine School of Health Sciences Aristotle University of Thessaloniki Thessaloniki Greece

2nd Department of Psychiatry National and Kapodistrian University of Athens Athens Greece

3rd Department of Psychiatry Faculty of Medicine School of Health Sciences Aristotle University of Thessaloniki Thessaloniki Greece

Antwerp Health Law and Ethics Chair AHLEC University Antwerpen Belgium

Centre for Youth Mental Health The Florey Institute for Neuroscience and Mental Health Parkville Victoria Australia

Clinical Department of Neurology Clinical Centre of Montenegro Podgorica Montenegro

Clinical Department of Psychiatry Clinical Centre of Montenegro Podgorica Montenegro

Department for Psychosis Treatment Vilnius Mental Health Center Vilnius Lithuania

Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland

Department of Clinic of Psychiatric Faculty of Medicine Vilnius University Vilnius Lithuania

Department of Medical and Health Sciences Faculty of Health Sciences Linköping University Linköping Sweden

Department of Molecular and Cellular Therapeutics Royal College of Surgeons in Ireland Dublin Ireland

Department of Neurosciences Katholieke Universiteit Leuven Leuven Belgium

Department of Neurosciences Mental Health and Sensory Organs Suicide Prevention Center Sant'Andrea Hospital Sapienza University of Rome Rome Italy

Department of Psychiatry and Mental Health Santa Maria University Hospital Lisbon Portugal

Department of Psychiatry and Mental Health University of Cape Town Cape Town South Africa

Department of Psychiatry and Narcology Riga Stradins University Riga Latvia

Department of Psychiatry and Psychotherapy Medical University of Vienna Vienna Austria

Department of Psychiatry and Psychotherapy Semmelweis University Budapest Hungary

Department of Psychiatry College of Medicine University of Ibadan Ibadan Nigeria

Department of Psychiatry Lokmanya Tilak Municipal Medical College Mumbai India

Department of Psychiatry National and Kapodistrian University of Athens School of Medicine Eginition Hospital Athens Greece

Department of Psychiatry Queen's University Providence Care Hospital Kingston Ontario Canada

Department of Psychiatry Royal College of Surgeons in Ireland Beaumont Hospital Dublin Ireland

Department of Psychiatry Ruhr University Bochum Bochum Germany

Department of Psychiatry Sainte Marguerite University Hospital Marseille France

Department of Psychiatry Samara Psychiatric Hospital Inpatient Unit Samara State Medical University Samara Russia

Department of Psychiatry School of Medicine University of Montenegro Podgorica Montenegro

Department of Psychiatry University of Florida Gainesville Florida USA

Department of Psychiatry University of Melbourne Parkville Victoria Australia

Department of Psychiatry University of Oviedo and Centro de Investigación Biomédica en Red de Salud Mental Oviedo Spain

Department of Psychiatry University of Turku Turku Finland

Department of Psychosocial Rehabilitation Vilnius Mental Health Center Vilnius Lithuania

Hallunda Psychiatric Outpatient Clinic Stockholm Psychiatric Southwest Clinic Karolinska Huddinge University Hospital Huddinge Sweden

IMPACT Strategic Research Centre School of Medicine Barwon Health Deakin University Geelong Australia

Institute of Mental Health Belgrade Serbia

Institute of Mental Health School of Medicine University of Belgrade Belgrade Serbia

MRC Unit on Risk and Resilience in Mental Disorders Department of Psychiatry and Mental Health University of Cape Town Cape Town South Africa

National Institute of Mental Health Klecany Czech Republic

Nyírő Gyula Hospital Budapest Hungary

Orygen The National Centre of Excellence in Youth Mental Health Parkville Victoria Australia

Psychiatry Department Diskapi Yildirim Beyazit Training and Research Hospital Ankara Turkey

Serbian Academy of Sciences and Arts Belgrade Serbia

Timone Institute of Neuroscience Marseille France

University Multiprofile Hospital for Active Treatment in Neurology and Psychiatry Sveti Naum Sofia Bulgaria

University of Medicine and Pharmacy of Târgu Mures Târgu Mures Romania

University of Medicine and Pharmacy of Timisoara Timisoara Romania

University Psychiatric Center Katholieke Universiteit Leuven Kortenberg Belgium

Western University London Ontario Canada

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