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C.03.03 Cognitive effects of antidepressants in depression
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C.03. Linking neurocircuitries and imaging to cognitive function in depression
C.03. Linking neurocircuitries and imaging to cognitive function in depression C.03.01 Cognition: from receptors to circuitry modulation T. Sharp1 ° 1 University of Oxford, Department of Pharmacology, Oxford, United Kingdom In patients with major depressive disorder, treatment with an antidepressant that targets serotonin, such as a selective serotonin reuptake inhibitor, promotes neuroadaptive changes that would be expected to enhance cognitive function. However, enhanced cognitive function is not always experienced by patients. The hypothesis that these drugs act through a simple increase in serotonin availability has advanced to the idea that an increase in serotonin signalling is just the starting point for a complex sequence of molecular and cellular changes that eventually bring about the full therapeutic effect. At the molecular level, these changes include activation of programmes of gene expression that lead to the strengthening of synaptic efficacy and connectivity, increased neuron formation and even switching neural networks into a more immature developmental state. It is thought that through this increase in plasticity, key neural circuits might be more easily remodelled by incoming cognitive and emotionally relevant stimuli. Much less is known about how such complex molecular changes might be expressed at the cellular level to modulate higher-order cognitions, specifically within the microcircuitry of the cerebral cortex. It is clear, however, that there are powerful interactions between serotonin and the cortex that are played out through multiple serotonin receptor subtypes, localised on distinct cortical neuron subpopulations. Greater knowledge of these interactions during the course of antidepressant treatment, specifically how they facilitate adaptations at the single cell level through to the neural network level, may help identify pharmacological approaches that will form the basis for novel serotonin-specific pro-cognitive drugs. Disclosure statement: Professor Sharp has received a basic science research grant from Lundbeck.
C.03.02 Neural networks for cognitive control as targets for treatment in major depression A. Etkin1 ° 1 Stanford University, Department of Psychiatry and Behavioral Sciences, Stanford, USA Abnormalities have been consistently identified in the prefrontal circuits involved in cognitive control (ie executive function) in major depressive disorder. An understanding of these brain networks may represent one way to optimise the application of currently available treatments for major depressive disorder, as well as to link the mechanisms of antidepressant actions to neural deficits involved in major depressive disorder beyond mood. This presentation will first discuss cognitive control circuitry in the context of the International Study to Predict Optimized Treatment in Depression (iSPOT-D). This practical antidepressant treatment trial is coupled with a suite of biomarkers that includes functional magnetic resonance imaging. Using functional magnetic resonance imaging in the neuroimaging sub-study of 102
patients, we found that pretreatment prefrontal activation during an executive function task predicted treatment response. In addition, there was differential activation in this region between healthy control individuals and future non-responders. These findings mirrored those using behavioural measures of executive function in the full sample of 1008 patients. In a parallel study of repetitive transcranial magnetic stimulation treatment for depression, we found that repetitive transcranial magnetic stimulation acts on cognitive control circuitry and that its effects are predicted by the magnitude of abnormalities within these circuits. Together, these findings identify cognitive control circuits as targets for the treatment of major depressive disorder and as predictors of treatment success. This may help inform treatment selection and guide the development of novel interventions. Disclosure statement: I have received research funding from Brain Resource.
C.03.03 Cognitive effects of antidepressants in depression J. Jaeger1 °
1 Cogstate,
VP Clinical Trials, New Haven, USA
Classical descriptions of major depressive disorder include impairments in mood, thought and action (motivation). Until recently, the major focus of treatment has been on the patient’s subjective experience of mood disorder, as this is the most proximate origin of the patient’s suffering. However, as a result, impairments in thought processes and cognition have been regarded as tertiary, an epiphenomenon of the secondary effects of depressed mood on motivation. More recently, new consideration has been given to the importance of cognitive dysfunction as a distinct aspect of major depressive disorder. This perspective is supported by evidence for modest but disabling residual cognitive dysfunction remaining following successful antidepressant treatment [1,2], and evidence that some antidepressants may exert a beneficial effect on cognition that is independent of their antidepressant effect [3]. With this new focus on cognitive dysfunction as an important biological and clinical dimension in major depressive disorder, this presentation will review recent clinical trials in the context of accumulating evidence that distinct pharmacological interventions may offer specific benefits for cognitive dysfunction in depression. This could lead to important reductions in functional disability among patients with major depressive disorder. With depression recognised as among the most disabling of all medical conditions worldwide, these conceptual developments are welcome prompts for the formulation of new medications, measurement tools and clinical trial designs in order to clarify the specific role of cognition in treatment and disease course. References [1] McIntyre, R.S., Cha, D.S., Soczynska, J.K., Woldeyohannes, H.O., Gallaugher, L.A., Kudlow, P., Alsuwaidan, M., Baskaran, A., 2013 Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety 30, 515–527. [2] Jaeger, J., Berns, S., Uzelac, S., Davis-Conway, S., 2006 Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res 145, 39−48. [3] McIntyre, R.S., Lophaven, S., Olsen, C.K., 2013 Randomized, doubleblind, placebo-controlled study of the efficacy of vortioxetine on cognitive dysfunction in adult patients with major depressive disorder (MDD). Poster presented at the American College of Neuropsychology 52nd Annual Meeting, Hollywood, Florida, USA. Disclosure statement: I am employed full time by Cogstate, Inc. and I own stock in Cogstate.
C.03. Linking neurocircuitries and imaging to cognitive function in depression
C.03. Linking neurocircuitries and imaging to cognitive function in depression C.03.01 Cognition: from receptors to circuitry modulation T. Sharp1 ° 1 University of Oxford, Department of Pharmacology, Oxford, United Kingdom In patients with major depressive disorder, treatment with an antidepressant that targets serotonin, such as a selective serotonin reuptake inhibitor, promotes neuroadaptive changes that would be expected to enhance cognitive function. However, enhanced cognitive function is not always experienced by patients. The hypothesis that these drugs act through a simple increase in serotonin availability has advanced to the idea that an increase in serotonin signalling is just the starting point for a complex sequence of molecular and cellular changes that eventually bring about the full therapeutic effect. At the molecular level, these changes include activation of programmes of gene expression that lead to the strengthening of synaptic efficacy and connectivity, increased neuron formation and even switching neural networks into a more immature developmental state. It is thought that through this increase in plasticity, key neural circuits might be more easily remodelled by incoming cognitive and emotionally relevant stimuli. Much less is known about how such complex molecular changes might be expressed at the cellular level to modulate higher-order cognitions, specifically within the microcircuitry of the cerebral cortex. It is clear, however, that there are powerful interactions between serotonin and the cortex that are played out through multiple serotonin receptor subtypes, localised on distinct cortical neuron subpopulations. Greater knowledge of these interactions during the course of antidepressant treatment, specifically how they facilitate adaptations at the single cell level through to the neural network level, may help identify pharmacological approaches that will form the basis for novel serotonin-specific pro-cognitive drugs. Disclosure statement: Professor Sharp has received a basic science research grant from Lundbeck.
C.03.02 Neural networks for cognitive control as targets for treatment in major depression A. Etkin1 ° 1 Stanford University, Department of Psychiatry and Behavioral Sciences, Stanford, USA Abnormalities have been consistently identified in the prefrontal circuits involved in cognitive control (ie executive function) in major depressive disorder. An understanding of these brain networks may represent one way to optimise the application of currently available treatments for major depressive disorder, as well as to link the mechanisms of antidepressant actions to neural deficits involved in major depressive disorder beyond mood. This presentation will first discuss cognitive control circuitry in the context of the International Study to Predict Optimized Treatment in Depression (iSPOT-D). This practical antidepressant treatment trial is coupled with a suite of biomarkers that includes functional magnetic resonance imaging. Using functional magnetic resonance imaging in the neuroimaging sub-study of 102
patients, we found that pretreatment prefrontal activation during an executive function task predicted treatment response. In addition, there was differential activation in this region between healthy control individuals and future non-responders. These findings mirrored those using behavioural measures of executive function in the full sample of 1008 patients. In a parallel study of repetitive transcranial magnetic stimulation treatment for depression, we found that repetitive transcranial magnetic stimulation acts on cognitive control circuitry and that its effects are predicted by the magnitude of abnormalities within these circuits. Together, these findings identify cognitive control circuits as targets for the treatment of major depressive disorder and as predictors of treatment success. This may help inform treatment selection and guide the development of novel interventions. Disclosure statement: I have received research funding from Brain Resource.
C.03.03 Cognitive effects of antidepressants in depression J. Jaeger1 °
1 Cogstate,
VP Clinical Trials, New Haven, USA
Classical descriptions of major depressive disorder include impairments in mood, thought and action (motivation). Until recently, the major focus of treatment has been on the patient’s subjective experience of mood disorder, as this is the most proximate origin of the patient’s suffering. However, as a result, impairments in thought processes and cognition have been regarded as tertiary, an epiphenomenon of the secondary effects of depressed mood on motivation. More recently, new consideration has been given to the importance of cognitive dysfunction as a distinct aspect of major depressive disorder. This perspective is supported by evidence for modest but disabling residual cognitive dysfunction remaining following successful antidepressant treatment [1,2], and evidence that some antidepressants may exert a beneficial effect on cognition that is independent of their antidepressant effect [3]. With this new focus on cognitive dysfunction as an important biological and clinical dimension in major depressive disorder, this presentation will review recent clinical trials in the context of accumulating evidence that distinct pharmacological interventions may offer specific benefits for cognitive dysfunction in depression. This could lead to important reductions in functional disability among patients with major depressive disorder. With depression recognised as among the most disabling of all medical conditions worldwide, these conceptual developments are welcome prompts for the formulation of new medications, measurement tools and clinical trial designs in order to clarify the specific role of cognition in treatment and disease course. References [1] McIntyre, R.S., Cha, D.S., Soczynska, J.K., Woldeyohannes, H.O., Gallaugher, L.A., Kudlow, P., Alsuwaidan, M., Baskaran, A., 2013 Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety 30, 515–527. [2] Jaeger, J., Berns, S., Uzelac, S., Davis-Conway, S., 2006 Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res 145, 39−48. [3] McIntyre, R.S., Lophaven, S., Olsen, C.K., 2013 Randomized, doubleblind, placebo-controlled study of the efficacy of vortioxetine on cognitive dysfunction in adult patients with major depressive disorder (MDD). Poster presented at the American College of Neuropsychology 52nd Annual Meeting, Hollywood, Florida, USA. Disclosure statement: I am employed full time by Cogstate, Inc. and I own stock in Cogstate.