Multiple signaling pathways are hypothesized to contribute to depression, including1,3:
- Monoaminergic,
- Glutamatergic, or
- GABAergic signaling pathways
The monoamine hypothesis has focused pharmacological treatment on the modulatory neurotransmitters serotonin, dopamine, and norepinephrine for the last six decades.4-6
Dysregulation of GABAergic and glutamatergic neurotransmission may also play a significant role in the pathophysiology of depression1,7
The GABA-glutamate balance is also thought to be critical to maintaining normal brain network function.5
Inhibitory and excitatory neurotransmission occur through the GABA and glutamate systems, respectively, affecting both intrinsic and extrinsic control of information flow in the brain.5
Acute stress can result in imbalances between GABAergic and glutamatergic signaling.2,7
Adaptation to chronic stress may lead to imbalances between GABAergic and glutamatergic signaling at lower levels, contributing to depression.2,7
PPD has a distinct pathophysiology that includes levels of neuroactive steroids that rise during pregnancy and fall significantly during the postpartum period.2,8
Neuroactive steroids, like allopregnanolone, are metabolites of steroid hormones that can rapidly modulate neuronal brain activity.8,9 The neuroactive metabolite of progesterone, allopregnanolone, has been shown to potentiate GABAA receptors.8
Some drivers of PPD are thought to include2,8:
- Fluctuating allopregnanolone levels during pregnancy and postpartum periods
- Dysregulated GABAergic signaling that may result in a loss of inhibitory signaling
The theories supporting the pathophysiology of MDD may not always explain PPD’s distinct mechanism of disease.2
There are currently no oral pharmacologic treatments that are FDA-approved for the treatment of PPD.10
Research suggests imbalances in the GABA-glutamate pathway could contribute to depression7
Endogenous positive allosteric modulators can regulate the activity of GABAA receptors.11
Glutamate receptors, like NMDA (N-methyl-D-aspartate) receptors, can modulate glutamatergic neurotransmission to help address the GABA-glutamate imbalance.7,11
Modulation of GABAA receptor signaling is one of the mechanisms that may affect network excitability and potentially impact mood.5,8
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References: 1. Sarawagi A, Soni ND, Patel AB. Glutamate and GABA homeostasis and neurometabolism in major depressive disorder. Front Psychiatry. 2021;12:637-863. doi:10.3389/fpsyt.2021.637863. 2. Meltzer-Brody S, Kanes SJ. Allopregnanolone in postpartum depression: role in pathophysiology and treatment. Neurobiol Stress. 2020;12:100212. 3. Otte C, Gold SM, Penninx BW, et al. Major depressive disorder. Nat Rev Dis Primers. 2016;2:16065. 4. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122(5):509-522. 5. Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102(1):75-90. 6. Elias E, Zhang AY, Manners MT. Novel pharmacological approaches to the treatment of depression. Life. 2022;12:196. doi: 10.3390/life12020196. 7. Fogaça MV, Duman RS. Cortical GABAergic dysfunction in stress and depression: New insights for therapeutic interventions. Front Cell Neurosci. 2019;13:87. 8. Payne JL, Maguire J. Pathophysiological mechanisms implicated in postpartum depression. Front Neuroendocrinol. 2019;52:165-180. 9. Maguire J. Neuroactive Steroids and GABAergic Involvement in the Neuroendocrine Dysfunction Associated With Major Depressive Disorder and Postpartum Depression. Front Cell Neurosci. 2019;13:83. 10. U.S. Food & Drug Administration. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process. Accessed March 15, 2023. 11. Martinez-Botella G, Ackley MA, Salituro FG, et al. Neural and synthetic neuroactive steroid modulators of GABAA and NMDA receptors. Ann Rep Med Chem. 2014;27-40.