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S.3.1 Clinical neuropsychopharmacology: focuson depression imaging in clinical research
Clinical Neuropsychopharmacology
Lectures
IS.3.11 Clinical neuropsychopharmacology: focus on depression imaging in clinical research H.S. Mayberg. Psychiatry and Neurology, Emory
Unioersity School of Medicine, Atlanta, GA, USA Converging clinical, biochemical, neuroimaging and postmortem evidence suggests that depression is unlikely a disease of a single brain region or neurotransmitter system. Rather, it is now generally viewed as a multidimensional, systems-level disorder affecting discrete but integrated pathways involving select cortical, subcortical and limbic sites and their related neurotransmitter and molecular mediators. While mechanisms driving this 'system dysfunction' are not yet characterized, they are thought likely to be multi-factorial, with genetic vulnerability, affective temperament, developmental insults and life stressors all considered important contributors. A series of functional neuroimaging studies considering these known risk factors has been synthesized into a data-driven depression model. In this neural systems model, a major depressive episode is considered the net result of maladaptive functional interactions among a well defined, highly integrated limbic-cortical network norm ally responsible for maintaining homeostatic emotional control in situations of cognitive and somatic stress. In this evolving depression model foci of 'network' dysfunction identified in the baseline depressed state are considered potential etiological abnormalities as well as sites of adaptive and maladaptive intrinsic compensatory processes, accommodating both the reported variations in pretreatment scan patterns and the well-recognized heterogeneity of depressive symptoms and pre-morbid functioning (i.e., mood, motor, cognitive, vegetativecircadian; neuroticism, early trauma). Treatments for depression are similarly viewed within this limbic-cortical system framework, where different modes of treatment modulate specific regional targets, resulting in a variety of complementary, adaptive chemical and molecular changes that re-establish a normal mood state. The synchronized modulation of these dysfunctional cortical-limbic pathways is considered critical for illness remission, regardless of treatment
modality, accommodating pharmacotherapy as well as cognitive and somatic interventions. Findings from converging studies of different depressed patient cohorts using a variety of functional neuroimaging methods (blood flow/glucose metabolism PET, BOLD are discussed in this context, emphasizing syndromal subtypes, illness and relapse risk markers, and treatment-specific response effects. Strategies to further characterize scan-pattern variability are highlighted as a critical next step towards the eventual development of imaging-based clinical algorithms to optimize treatment selection in individual patients.
References [1] Mayberg HS, Brannan SE, Mahurin RK, McGinnin S,. Regional Metabolic Effects of Fluoxetine in Major Depression: Serial Changes and Relationship to Clinical Response. Biol Psychiatr 48: 830-843, 2000. [2] Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, Mayberg H. Modulation of cortical-limbic pathways in major depression: treatment specific effects of Cognitive Behavioral Therapy. Arch Gen Psychiatr 61: 34-41, 2004. [3] Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple KK, Kennedy S, Segal Z, Rafi-Tari S. Limbic-Frontal Circuitry in Major Depression: A Path Modeling Metanalysis. Neuroimage 22: 409-418, 2004. [4] Mayberg HS. Modulating Dysfunctional LimbicCortical Circuits in Depression: Towards Development of Brain-based Algorithms for Diagnosis and Optiraised Treatment. Br Med Bull 65:193-207, 2003.
Endophenotypes for affective disorders S. Modell. Bristol-Myers Squibb, Munich, Germany The search for endophenotypes in psychiatry has regained importance in the last few years since it became clear that the current classification systems have not been too useful in linkage and association studies. The behavioral phenotype alone (e.g. psychopathology) may not be optimal for dissecting diseases that have complex genetic underpinnings. The term "endophenotype" had already been introduced over 30 years ago and has
Lectures
IS.3.11 Clinical neuropsychopharmacology: focus on depression imaging in clinical research H.S. Mayberg. Psychiatry and Neurology, Emory
Unioersity School of Medicine, Atlanta, GA, USA Converging clinical, biochemical, neuroimaging and postmortem evidence suggests that depression is unlikely a disease of a single brain region or neurotransmitter system. Rather, it is now generally viewed as a multidimensional, systems-level disorder affecting discrete but integrated pathways involving select cortical, subcortical and limbic sites and their related neurotransmitter and molecular mediators. While mechanisms driving this 'system dysfunction' are not yet characterized, they are thought likely to be multi-factorial, with genetic vulnerability, affective temperament, developmental insults and life stressors all considered important contributors. A series of functional neuroimaging studies considering these known risk factors has been synthesized into a data-driven depression model. In this neural systems model, a major depressive episode is considered the net result of maladaptive functional interactions among a well defined, highly integrated limbic-cortical network norm ally responsible for maintaining homeostatic emotional control in situations of cognitive and somatic stress. In this evolving depression model foci of 'network' dysfunction identified in the baseline depressed state are considered potential etiological abnormalities as well as sites of adaptive and maladaptive intrinsic compensatory processes, accommodating both the reported variations in pretreatment scan patterns and the well-recognized heterogeneity of depressive symptoms and pre-morbid functioning (i.e., mood, motor, cognitive, vegetativecircadian; neuroticism, early trauma). Treatments for depression are similarly viewed within this limbic-cortical system framework, where different modes of treatment modulate specific regional targets, resulting in a variety of complementary, adaptive chemical and molecular changes that re-establish a normal mood state. The synchronized modulation of these dysfunctional cortical-limbic pathways is considered critical for illness remission, regardless of treatment
modality, accommodating pharmacotherapy as well as cognitive and somatic interventions. Findings from converging studies of different depressed patient cohorts using a variety of functional neuroimaging methods (blood flow/glucose metabolism PET, BOLD are discussed in this context, emphasizing syndromal subtypes, illness and relapse risk markers, and treatment-specific response effects. Strategies to further characterize scan-pattern variability are highlighted as a critical next step towards the eventual development of imaging-based clinical algorithms to optimize treatment selection in individual patients.
References [1] Mayberg HS, Brannan SE, Mahurin RK, McGinnin S,. Regional Metabolic Effects of Fluoxetine in Major Depression: Serial Changes and Relationship to Clinical Response. Biol Psychiatr 48: 830-843, 2000. [2] Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, Mayberg H. Modulation of cortical-limbic pathways in major depression: treatment specific effects of Cognitive Behavioral Therapy. Arch Gen Psychiatr 61: 34-41, 2004. [3] Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple KK, Kennedy S, Segal Z, Rafi-Tari S. Limbic-Frontal Circuitry in Major Depression: A Path Modeling Metanalysis. Neuroimage 22: 409-418, 2004. [4] Mayberg HS. Modulating Dysfunctional LimbicCortical Circuits in Depression: Towards Development of Brain-based Algorithms for Diagnosis and Optiraised Treatment. Br Med Bull 65:193-207, 2003.
Endophenotypes for affective disorders S. Modell. Bristol-Myers Squibb, Munich, Germany The search for endophenotypes in psychiatry has regained importance in the last few years since it became clear that the current classification systems have not been too useful in linkage and association studies. The behavioral phenotype alone (e.g. psychopathology) may not be optimal for dissecting diseases that have complex genetic underpinnings. The term "endophenotype" had already been introduced over 30 years ago and has