The impact of brain network dysregulation in depression

To date, the pharmacological treatment of depression has been focused on monoamine regulation1-3

For nearly 60 years, the monoamine hypothesis has focused pharmacological treatment on the modulatory neurotransmitters serotonin, dopamine, and norepinephrine.1-3

Additional hypotheses suggest that other neurotransmitters may be involved in the pathophysiology of depression: 

  • Amino acid hypothesis of depression: Non-monoaminergic neurotransmitter systems, including glutamate and GABA4
  • Neuropeptide hypothesis of depression: Neuropeptides such as corticotropin-releasing hormone, substance P, neuropeptide Y, and galanin4,5
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Watch this video to learn about the neurochemical systems, including excitatory and inhibitory signaling, that may play a role in depression.

Another leading hypothesis of depression is the dysregulation of GABAergic and glutamatergic neurotransmission6

Inhibitory and excitatory neurotransmission occur through the GABA and glutamate systems, respectively, affecting both intrinsic and extrinsic control of information flow in the brain.6,7

  • Preclinical and clinical evidence has shown a deficiency in GABAergic neurotransmission in depression6
  • Glutamate-mediated excitatory neurotransmission has also been shown to be altered in depression6
  • Deficient GABAergic signaling may not properly tone down excitatory signaling in the brains of patients experiencing a depressive episode6-9

GABA=gamma aminobutyric acid.

Endogenous positive allosteric modulators can regulate the activity of GABAA receptors10-13

Synaptic and extrasynaptic GABAA receptors may help maintain neuronal network function.7,14

Modulation of GABAA receptor signaling can affect network excitability and potentially impact mood.7,12-18

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