Understanding Cognitive Disability in Schizophrenia Cameron S. Carter MD University of California at Davis

Schizophrenia is common and can lead to lifelong disability 1% of population world wide Males and females equally affected but females have later onset and better functional outcome Onset in late adolescence, early adulthood Loss of function, inability to achieve expected function

Etiology:Genetics Highly heritable Risk increases with relationship e.g. 10% for first degree relative or fraternal twin, 50% concordance for monozygotic twin Environmental factors certain but poorly characterized (intrauterine malnutrition, viral illnesses, perinatal insults, drug exposure) Gene environment interactions affect brain development and function

Schizophrenia as a Developmental Disorder Most strongly associated risk genes (e.g. NRG, DISC1, RGS4) affect early brain development People who go on to develop schizophrenia show lower school achievement and more behavioral problems during childhood Onset during early adolescence during massive brain development Environmental risks factors have their impact during critical developmental windows (e.g. maternal influenza, early, heavy cannabis use, late) Some environmental risk factors may be mediated through activation of maternal immune system that may in turn impact brain development and synaptic function

Symptoms At least 4 weeks of 2 of the following Hallucinations Delusions Negative symptoms Disorganization Minimum duration of 6 months of continuous signs of illness

Alterations in dopamine neurotransmission C11 Racolpride displacement reflects DA release

Increased subcortical DA related to psychosis

Cognition In Schizophrenia Present at onset and throughout the life span Impaired cognition is a strong predictor of disability in schizophrenia (e.g. Green 1997). Currently available treatments have little impact on cognitive disability in schizophrenia Perhaps the most amenable to investigation using modern, non invasive neuroscientific tools Promising for biomarker development

Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia

Effects of hemodynamic activation on BOLD signal in the brain: a) paramagnetic properties of Hb and b) overly zealous regulation of perfusion of the brain

Metanalysis of 41 fMRI Studies of Executive Functions Healthy Controls Schizophrenia

Impairment of Top Down Control in Schizophrenia: Functional Connectivity Yoon, Minzenberg, Ursu, and Carter 2008 American J. Psychiatry

Courtesy of David Lewis MD

Improved Management to Improve Functional Outcomes in Schizophrenia Early intervention important for improving functional outcome Rehabilitative therapies e.g. supportive employment and education improve outcomes Develop novel medication treatments targeting cognition Validate neurorehabilitation approaches