Apathy and social withdrawal in schizophrenia: A collaborative study on the impact of psychotherapeutic treatments on the fronto-striatal networks of the motivation and social interactions. – MOTIVASOCIAL

Negative symptoms of schizophrenia are the primary cause of patients’ disability, resulting in major difficulties in everyday functioning and poor quality of life. Strikingly, no pharmacological treatment adequately improves these symptoms. Conversely, several psychotherapeutic interventions exist and have shown benefits for different aspects of negative symptoms, however, these effects are highly variable from patient to patient and their mechanisms and neural underpinnings remain heavily understudied. The main aim of the present project is to assess which symptoms, underlying mechanisms, and neural bases are affected by such therapeutic approaches, in order to develop individually targeted treatments. Our project will allow identifying and predicting treatment responses in different patients based on their baseline symptoms, their task performance and the functional levels of their dopamine and serotonin systems. The current concept of negative symptoms distinguishes between two dimensions: apathy (lack of motivation that include asociality and anhedonia) and diminished expression (emotional and verbal). Dysfunctions in different sets of processes relying on different brain regions and neurotransmitters are thought to underlie these dimensions. The apathy dimension relies primarily on motivational subcomponents, such as reward anticipation, subtended by striatal activity and dopaminergic projections. Decreased expressions appears rather related to deficits in recognition of emotions and intentions of others, which directly interferes with social functioning leading to social withdrawal that could be underpinned by the limbic brain networks and the serotonergic projections. Our project will verify this new hypothesis, which will extend our knowledge of the negative symptoms of schizophrenia. The project will use two promising psychotherapeutic approaches to reduce the symptoms described. The Positive Emotion Program for Schizophrenia (PEPS) targets the apathy dimension and the underlying problems in motivation and pleasure processing. The Social Cognition and Interaction Training (SCIT) targets the social functioning deficits, by training patient to reduce their negative bias concerning emotions and intentions of others in everyday life to reduce social withdrawal. Before and after the therapeutic interventions patients will undergo a detailed clinical evaluation assessing symptom levels, cognition, socio-cognitive performance and pleasure experience. They will also perform three well-validated experimental tasks during an fMRI session before and after the intervention. The tasks target the mechanisms and brain areas relevant for symptom formation, which we expect to respond to the interventions: reward anticipation, emotion processing and social decision-making. A subgroup of patients will undergo simultaneous PET-fMRI to assess presynaptic dopamine and serotonin activity. This is an international collaborative project, run at three research sites (Lyon, Saint-Etienne and Geneva), and including clinical experts in the pathophysiology and treatment development of schizophrenia, as well as researchers specialising in neural and molecular bases of patients’ symptoms. It will allow recruiting 180 patients across the three sites, a number only achievable through a collaborative effort. We expect several direct findings in the scientific domain (e.g. the role of serotonin in negative symptoms; neural bases of different therapy effects), straightforward results for treatment improvement and development (e.g. which mechanisms, brain areas and neurotransmitters to target) as well as potential for transdiagnostic application (e.g. apathy and reduced pleasure experience in bipolar disorder and Parkinson’s disease). The project will provide an ideal environment for training young researchers in psychiatry using experimental approaches of integrative Neuroscience to better understand mental illnesses in order to better treat them.