According to the World Health Organization, depression has now surpassed HIV, AIDS, malaria, diabetes, and war as the leading cause of disability. Current antidepressants may take weeks to months to be effective. Unfortunately, one-third of patients are still unresponsive, and are called “treatment-resistant.” However, there are other options available.
Ketamine, possibly the most widely used anesthetic agent in the world, has been shown by numerous studies to have rapid antidepressant effects when used off-label. The full mechanism by which ketamine induces these therapeutic effects is still a mystery. What researchers do understand is that increased levels of brain derived neurotrophic factor (BDNF), a protein that plays a role in the growth and maintenance of neurons, is involved. But how and where does ketamine increase BDNF?
Brain-derived neurotrophic factor is a critical regulator of neural development. It is a protein with effects on the central nervous system as well as the endocrine and immune systems. BDNF favors the survival of existing neurons, and promotes the growth and differentiation of new ones. Binding of BDNF to its receptor promotes neuronal survival in the adult brain. BDNF has already been shown to enhance mental abilities at the same time as acting against anxiety and depression.
A recent study in 2017 suggests that HDAC5, an enzyme affecting DNA and chromosomes, regulates the antidepressant effects of ketamine through a process called phosphorylation, which regulates protein function. Ketamine influences the transcription (the process by which DNA is turned into RNA) of BDNF and increases BDNF levels in the central nervous system.
Additionally, a study in 2015 demonstrated that the antidepressant effects of ketamine are based on the release of BDNF and the activation of the L-type voltage-dependent calcium channels (VDCC). Researchers found that the release of BDNF regulates the antidepressant effects of ketamine, further clarifying the underlying mechanisms that ketamine utilizes.
Furthermore, researchers observed in another 2015 study that dysfunctional levels of BDNF may be linked to depression, and that ketamine treatment can produce a positive effect within certain pathways of the brain, such as in the prefrontal cortex and nucleus accumbens. In this animal study, rats were divided into four groups: saline+deprived, saline+non-deprived, ketamine+deprived, and ketamine+non-deprived. Ketamine infusions were administered daily for 14 days. Researchers then observed the animals’ brain structures. They observed that the deprived rats had reduced levels of BDNF in the amygdala, hippocampus and nucleus accumbens. The ketamine reversed the levels of BDNF in the amygdala and nucleus accumbens. This is important because the amygdala plays a critical response in fear and strong emotions, while the nucleus accumbens is essential in motivation, aversion, reward, and learning.
The rapid-acting antidepressant effects of ketamine can depend on the rapid synthesis of BDNF.
In addition to ketamine’s effect on the default mode network, neurons, brain waves, glutamate neurotransmitter, and inflammation, by understanding ketamine’s impact on BDNF, we can gain a deeper insight into the mystery of how our brain works. Ultimately, as Socrates once said, “To know thyself is the beginning of wisdom.”
References:
Choi, Miyeon, et al. “Ketamine Induces Brain-Derived Neurotrophic Factor Expression via Phosphorylation of Histone Deacetylase 5 in Rats.” Biochemical and Biophysical Research Communications, vol. 489, no. 4, 2017, pp. 420–425., doi:10.1016/j.bbrc.2017.05.157.
Lepack, A. E., et al. “BDNF Release Is Required for the Behavioral Actions of Ketamine.” International Journal of Neuropsychopharmacology, vol. 18, no. 1, 2014, doi:10.1093/ijnp/pyu033.
Réus, Gislaine, et al. “Ketamine Treatment Partly Reverses Alterations in Brain Derived- Neurotrophic Factor, Oxidative Stress and Energy Metabolism Parameters Induced by an Animal Model of Depression.” Current Neurovascular Research, vol. 12, no. 1, 2015, pp. 73–84., doi:10.2174/1567202612666150122122924.
According to the World Health Organization, depression has now surpassed HIV, AIDS, malaria, diabetes, and war as the leading cause of disability. Current antidepressants may take weeks to months to be effective. Unfortunately, one-third of patients are still unresponsive, and are called “treatment-resistant.” However, there are other options available.
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