Speaker: Anissa Abi-Dargham, USA

Objectives: Molecular imaging with Positron Emission Tomography (PET) has been used to examine various aspects of dopaminergic transmission in schizophrenia and have converged to show excess striatal presynaptic release and activity, as well as functional supersensitivity of striatal D2 receptors. The striatal dysfucntion occurs early on in the course of the disease and predicts conversion to psychosis. More recently imaging studies have documented alterations in extrastriatal dopamine. We will present here the overall combined data from multiple studies done to date to extract a comprehensive topographical mapping of the dopaminergic dysfunction in schizophrenia and its complex relationship to clinical symptom domains. Methods: PET imaging studies using D2/3 radiotracers combined with the amphetamine challenge in patients with schizophrenia and matched healthy controls to image striatal and extrastriatal capacity for dopamine release. Results: Dopamine release is significantly reduced in patients with schizophrenia compared to controls matched for age, gender, ethnicity, smoking, parental socioeconomic status and catechol-O-methyltransferase (COMT) genotype in dorso-lateral prefrontal cortex (DLPFC) as well as in all cortical and in most extrastriatal regions. In particular the midbrain DA cell body region (i.e. substantia nigra and ventral tegmental area) showed a substantial blunting of release in drug-naïve and drug-free patients, compared to controls. Conclusions: These observations of opposite presynaptic dopaminergic dysfunction between striatal and extrastriatal regions suggest that the striatal excess may not be driven by activity levels of midbrain DA cells but may result from abnormal striatal local regulation of presynaptic DA release, affecting specifically the associative striatum, region which shows largest magnitude of excess DA. Furthermore alterations in dopaminergic signaling in opposing directions may have a dual effect on learning across functional domains by weakening learning from salient or relevant signals and reinforcing stimulus independent signals, thus explaining different symptom domains. 09.45 – 11.30 S1: Uncovering the circuitry of depression and how it guides the development of novel treatment strategies Chair: Anthony Grace, USA Co-Chair: Heong-Jeong Lee, Republic of Korea Speaker 1: Gitte Moos Knudsen, Denmark Title: Functional and molecular studies of human brain serotonergic circuits in depression Abstract Functional magnetic resonance imaging (fMRI) studies have consistently pointed towards amygdala, medial prefrontal cortex and subgenual cortex/anterior cingulate as key structures in the circuit involved in depression. Early fMRI studies showed that sertraline intervention in depressive patients was associated with increased corticolimbic connectivity, thereby possibly increasing the regulatory influence of cortical mood-regulating regions over limbic regions (Anand et al, 2005). Pharmacological intervention with the selective serotonin reuptake inhibitor (SSRI) escitalopram results in a selective modulation of the intrinsic network connectivity associated with the medial prefrontal-limbic system (Wang et al, 2015). However, also non-pharmacological intervention with bright light exposure significantly affects amygdala-prefrontal reactivity and communication, an effect partly moderated by 5-HTTLPR genotype (Fisher et al, 2014). That is, the corticolimbic circuit is sensitive to both SSRI and to bright light intervention, supporting the relevance of these regions for mood disorders and the associated treatment. Molecular brain imaging studies have, on the other hand, shown less regional specificity. Patients with seasonal affective disorder, investigated both in their symptom-free phase in the summer and in the winter when they had season-related depression, failed to down-regulate their cerebral sertonin transporter (5-HTT) binding globally, as opposed to individuals resilient to seasonal affective disorder. In healthy individuals, light therapy given in the winter was associated with 12% decreased 5-HTT binding in the anterior cingulate relative to placebo. And individuals at high familial risk for mood disorders had a 35% reduction in 5-HTT binding in dorsolateral prefrontal cortex and a tendency to reduction in anterior cingulate. In conclusion, whereas several fMRI studies identify amygdala, medial prefrontal cortex and subgenual cortex/anterior cingulate as key structures, some molecular imaging studies of 5-HTT binding suggest that dorsolateral prefrontal cortex,Functional magnetic resonance imaging (fMRI) studies have consistently pointed towards amygdala, medial prefrontal cortex and subgenual cortex/anterior cingulate as key structures in the circuit involved in depression. Early fMRI studies showed that sertraline intervention in depressive patients was associated with increased corticolimbic connectivity, thereby possibly increasing the regulatory influence of cortical mood-regulating regions over limbic regions (Anand et al, 2005). Pharmacological intervention with the selective serotonin reuptake inhibitor (SSRI) escitalopram results in a selective modulation of the intrinsic network connectivity associated with the medial prefrontal-limbic system (Wang et al, 2015). However, also non-pharmacological intervention with bright light exposure significantly affects amygdala-prefrontal reactivity and communication, an effect partly moderated by 5-HTTLPR genotype (Fisher et al, 2014). That is, the corticolimbic circuit is sensitive to both SSRI and to bright light intervention, supporting the relevance of these regions for mood disorders and the associated treatment. Molecular brain imaging studies have, on the other hand, shown less regional specificity. Patients with seasonal affective disorder, investigated both in their symptom-free phase in the summer and in the winter when they had season-related depression, failed to down-regulate their cerebral sertonin transporter (5-HTT) binding globally, as opposed to individuals resilient to seasonal affective disorder. In healthy individuals, light therapy given in the winter was associated with 12% decreased 5-HTT binding in the anterior cingulate relative to placebo. And individuals at high familial risk for mood disorders had a 35% reduction in 5-HTT binding in dorsolateral prefrontal cortex and a tendency to reduction in anterior cingulate. In conclusion, whereas several fMRI studies identify amygdala, medial prefrontal cortex and subgenual cortex/anterior cingulate as key structures, some molecular imaging studies of 5-HTT binding suggest that dorsolateral prefrontal cortex,