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The Biological Mechanisms Underlying Major Depressive Disorder - Coggle…

- - - - The effectiveness of MAO inhibitors for the treatment of depression was discovered by chance, as patients treated with Iproniazid had side effects like euphoria, increased appetite and improved sleep
      - Furter MAO inhibitors were studied such as Moclobemide, but were replaced by tricyclic antidepressant drugs (TCA)
      - 1959, Imipramine approved by FDA, inhibits presynaptic NE and 5-HT reuptake transporters and blocking things like alpha1 and muscarinic receptors
        Severe side effects like memory impairment and drowsiness
  - - - Is a NMDA receptor antagonist showing antidepressant effects after low dose intravenous administration and exerted in hours rather than weeks
      - Due to the side effects and potential for abuse, further studies are ongoing
    - - Ketamine blocks NMDA receptors on the Gabaergic interneurons reducing the inhibition of glutamate release in glutamatergic neurons
      - Leads to a glutamate surge followed by the binding to AMPA receptors
      - Increased stimulation of AMPA receptors leads to several second messenger cascades which leads to increased neuroplasticity
      - Increase of glutamate levels is responsible of cell depolarization with a release of BDNF, increases neuroplasticity and neurodevelopment
- - - - The humoral pathway which involves the cytokines passage through leaky regions in the BBB
      - The neural pathway, involving the binding of afferent nerves fibers by the cytokines which stimulates ascending fiber
      - The cellular pathway which involves the trafficking of immune cells to the brain vasculature and parenchyma
      - The brain neurotransmitters are regulated by the increased levels of cytokines and pro-inflammatory modulators involved in the sickness behavior
- - - - Lower serum levels
      - Reduce hippocampal activity
      - Increased risk of suicide
      - Increased risk of developing depression in subjects exposed to early life stress
    - - Serotonin system and BDNF are related
      - BDNF promotes survival and morphological differentiation of 5-HT neurons, a
      - Infusion of BDNF increase the gene expression of of the rate limiting enzyme in 5-HT synthesis and upregulates 5-HT uptake and its activity dependent release
      - The link of BDNF and serotonin systems may explain the temporal window needed by antidepressant drugs to exert their activity