Aakshi Sanchorawala

Background: Perinatal depression, the most common childbirth complication, is classified as “Major Depressive Disorder, with peripartum onset” in the DSM-5. Perinatal Depression is featured with intense sadness and anxiety in the mother and can prevent her from mother-infant bonding and decrease the chance of the child being breastfed. If left untreated, it can result in “low birth weight and impaired social, cognitive, and emotional development in the baby.”^1,2 More than a half million women each year develop a depressive disorder. Ketamine has been shown to help ⅓ of patients with treatment-resistant depression achieve remission³. Because of the lack of research done on pregnant women, ketamine’s long-term effects on mothers as well as its effect on fetal brains in the gestational environment during delivery remains unknown.

Objective: In this narrative review, the mechanism in which ketamine works to enhance hippocampal synaptic plasticity in women to reduce and reverse depressive symptoms is explored.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using the following keywords: “perinatal depression”, “mTOR signaling”, “synaptic plasticity”, and “hippocampal plasticity”.

Results: Results showed that ketamine works by blocking NMDA receptors⁴, which then increases glutamate levels to stimulate local protein synthesis. This leads to a cascade of processes that result in the rapid proliferation of dendritic spines. Low-dose ketamine was shown to cause a reduction in anxiety and depression-like behaviors. These treatments, also, reversed the depression-induced decrease in hippocampal synaptic proteins, Syn-1, BDNF, and PSD-95⁵, verifying ketamine’s ability to play a role as an antidepressant. In the hippocampal neurons, ketamine was shown to induce an increase in apoptotic mechanisms, reactive oxygen species, and Ca²⁺ concentrations¹⁰. Administration of rapamycin, a known mTOR pathway inhibitor^6,7,8, caused a reversal of the apoptotic mechanisms seen by increasing Bcl-2 and decreasing Bax and Caspase-3 levels⁶. Therefore, ketamine was proven to upregulate apoptosis in hippocampal neurons through the mTOR pathway. Within the mTOR pathway, ketamine mimicked antidepressant effects by preventing the phosphorylation downstream regulators, 4EBP-1 and 4EBP-2, keeping them from dissociating and thereby stopping the initiation of mRNA translation⁸. Lastly, in clinical use, co-administration with guanosine, an endogenous glutamatergic neuromodulator, was shown to enhance the speed and efficiency of ketamine mTORC1 signaling shown by an increased dendritic density and hippocampal synaptic proteins⁹. When it comes to perinatal depression, prevention and immediate treatment are keys to successfully recovering. Potentiation through coadministration with agonists could avoid early detrimental effects, including avoiding breastfeeding.

Conclusion: Studies have found ketamine’s ability to prevent and reduce depressive symptoms through the inhibition of 4EBP-1 and 4EBP-2 proteins in the mTORC1 pathway, which in turn affects hippocampal synaptic plasticity. While ketamine is classically used as an anesthetic, its antidepressant effects can be clinically potentiated with co-administration of agonists, such as guanosine, to reduce and treat perinatal depression more efficiently and effectively. Further research into ketamine’s long-term effects on the fetal brain during gestation should be conducted to increase confidence in its use in clinical practice.

Works Cited:

1. Payne JL, Maguire J. Pathophysiological mechanisms implicated in postpartum depression. Front Neuroendocrinol. 2019;52:165-180. doi:10.1016/j.yfrne.2018.12.001
2. Van Niel MS, Payne JL. Perinatal depression: A review. Cleve Clin J Med. 2020;87(5):273-277. doi:10.3949/ccjm.87a.19054
3. Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: A paradigm shift for depression research and treatment. Neuron. 2019;101(5):774-778. doi:10.1016/j.neuron.2019.02.005
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7. Averill LA, Averill CL, Gueorguieva R, et al. mTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression. J Affect Disord. 2022;303:91-97. doi:10.1016/j.jad.2022.01.104
8. Aguilar-Valles A, De Gregorio D, Matta-Camacho E, et al. Antidepressant actions of ketamine engage cell-specific translation via eIF4E.          Nature. 2021;590(7845):315-319. doi:10.1038/s41586-020-03047-0
9. Camargo A, Dalmagro AP, Delanogare E, et al. Guanosine boosts the fast, but not sustained, antidepressant-like and pro-synaptogenic effects of ketamine by stimulating mTORC1-driven signaling pathway. Eur Neuropsychopharmacol. 2022;57:15-29. doi:10.1016/j.euroneuro.2021.12.010