Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review

Abstract

Brain-derived neurotrophic factor (BDNF) is critical for neuroplasticity, synaptic transmission, and neuronal survival. Studies have implicated it in the pathophysiology of depression, as its expression is significantly reduced in brain areas such as the prefrontal cortex and hippocampus in patients with depression. Our narrative review focuses on the relationship between BDNF, ketamine, and esketamine, specifically by summarizing human studies investigating BDNF variations in patients treated with these two drugs. BDNF plays a pivotal role in neuroplasticity and neurotrophic mechanisms that can be enhanced by traditional antidepressants, which have been shown to increase BDNF levels both peripherally and in targeted brain regions. Ketamine and its S-enantiomer, esketamine, exert both rapid and sustained antidepressant effects through activation of glutamate-related pathways, with neurotrophic effects involving BDNF, as demonstrated in experimental studies. However, clinical findings have shown mixed results, with most indicating an increase in plasma BDNF in patients treated with intravenous ketamine, although some studies contradict these findings. In addition to this, there are few studies of BDNF and esketamine. Currently, the limited number of studies suggests the need for further research, including larger sample sizes and investigations of BDNF and intranasal esketamine, which has been approved by several regulatory agencies for the treatment of treatment-resistant depression.

Keywords: BDNF; esketamine; ketamine; major depressive disorder; treatment-resistant depression.

Figure 1

Mechanisms of ketamine action involving brain-derived neurotrophic factor (BDNF). Ketamine acts as an antagonist of the N-methyl-D-aspartate (NMDA) receptor. The antagonism of NMDA receptors (NMDAR) is particularly important at the level of GABAergic interneurons (1), especially those expressing the GluN2b subunit. Indeed, this antagonism leads to a reduction in their activity, which normally inhibits glutamatergic pyramidal neurons (Glutamate Neurons). Consequently, the activity of these pyramidal neurons increases, leading to the release of glutamate, which primarily affects AMPA receptors (AMPAR) (A) and L-type voltage-dependent Ca2+ channels (L-VDCCs) (B), with a subsequent increase in the production of BDNF. Specifically, the activation of AMPAR leads to the phosphorylation of methyl CpG binding protein 2 (MeCP2), resulting in an increased transcription of genes such as BDNF. Additionally, NMDA receptor activation inhibits Eukaryotic elongation factor 2 (eEF2) kinase (2) (eEF2K), which normally phosphorylates eEF2, thereby inhibiting BDNF production. The dephosphorylation of eEF2 thus results in increased BDNF production. Furthermore, microglia (3) also play a role, with ketamine increasing the expression of Nuclear Receptor Binding Protein 1 (NRBP1) and phosphorylated cAMP response element-binding protein (CREB), leading to an increased transcription of BDNF. The increase in BDNF through these mechanisms stimulates the mammalian target of rapamycin complex 1 (mTORC1) signaling pathways, promoting increased protein synthesis and the formation of new dendritic spines. Additionally, this leads to the upregulation of hippocampal AMPAR subunits GluA1 and GluA2, and the activation of tropomyosin receptor kinase B (TrkB), which triggers intracellular pathways that contribute to synaptogenesis and the enhancement of NMDA receptor activity.

Figure 2

Binding of brain-derived neurotrophic factor (BDNF) to Tropomyosin Receptor Kinase B (TrkB) and the resulting neurotrophic mechanisms involved in depression. When BDNF binds to TrkB, it induces dimerization and autophosphorylation of its tyrosine kinase (1). This phosphorylation activates several intracellular signaling pathways (2), including the mammalian target of rapamycin complex 1 (mTORC1), phosphoinositide 3-kinase (PI3K), phospholipase C gamma (PLCγ), and mitogen-activated protein kinase (MAPK). These pathways regulate processes such as neuroplasticity, increasing cellular transcription and enhancing synaptogenesis (3). The importance of the BDNF-TrkB interaction for ketamine’s antidepressant action is highlighted by the fact that animal models treated with anti-BDNF antibodies, or knockout (KO) models for the BDNF or TrkB gene, or with selective TrkB inhibitors (TrkBi) (4), do not respond to ketamine’s antidepressant effects.

Figure 3

Rapid and sustained mechanisms of ketamine and BDNF on synaptic plasticity.