Linking the cytokine and neurocircuitry hypotheses of depression: a translational framework for discovery and development of novel anti-depressants.
Recent studies suggest a model of depression that links the cytokine hypothesis from the field of psychoneuroimmunology with the neurocircuitry hypothesis derived from burgeoning insight into neurophysiological changes observed in depressed patients. According to the neurocircuitry hypothesis of depression, failure of homeostatic synaptic plasticity in cortical-striatal-limbic nodes of a distributed network of neural circuits involving the sub-genual anterior cingulate cortex is responsible for core symptoms of depression: loss of interest or pleasure (anhedonia) and depressed mood (sadness). According to the cytokine hypothesis of depression, inflammatory cytokines act on neural circuits to evoke the behavioral and physiological changes observed in depression. Synthesis of these hypotheses implicates cytokines released during injury, infection, illness, or psychological stress as a cause of dysregulated synaptic plasticity in cortical-striatal-limbic circuits implicated in depression. These neural circuits process affective and reward-based information for optimal cost-benefit decision-making, a function that may link cytokine-evoked changes in synaptic plasticity to translatable measures of specific behavioral impairments observed in depressed patients. This viewpoint outlines evidence linking the cytokine and neurocircuitry hypotheses of depression to offer a translational model of major depressive disorder suitable for novel drug discovery and development.
Piser
Timothy M
TM
CNS Discovery Research, AstraZeneca Pharmaceuticals, Wilmington, DE, USA. timothy.piser@astrazeneca.com
D000928:Antidepressive Agents / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology* / Q000523:psychology; D006801:Humans; D008032:Limbic System / Q000187:drug effects / Q000503:physiopathology; D017072:Neostriatum / Q000187:drug effects / Q000503:physiopathology; D009415:Nerve Net / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000276:immunology*
D000928:Antidepressive Agents; D016207:Cytokines