Ahmad Alftieh, Ottawa ON – A recent paper published in the prestigious journal Nature by Dr. Argel Aguilar-Valles, an Assistant Professor at Carleton University, and colleagues in October of this year looked into the molecular mechanisms that mediate the antidepressant effects of ketamine for major depressive disorder. Major depressive disorder is a common mental health disorder that is characterized by a persistently depressed mood and long-term loss of pleasure or interest in life. It is one of the leading causes of disability worldwide and is often accompanied by other symptoms such as disturbed sleep, feelings of guilt or inadequacy, and suicidal thoughts.

 

Finding an effective pharmacological treatment for major depressive disorder has been a major challenge for researchers as more than thirty percent of patients are resistant to the first line of treatment, which is selective serotonin reuptake inhibitors (SSRI). Decades of research has been conducted to combat major depressive disorder and only recently the therapeutic potential of ketamine was discovered which harnessed a lot of attention in the field, leading to its approval for use in supervised clinical settings in Canada earlier this year.

 

Ketamine is a medication developed in the 1960s to induce loss of consciousness or anesthesia. It is used to relieve pain and produce relaxation in humans and animals. Research shows that sub-anesthetic doses of ketamine can provide rapid (within hours) and long-lasting (up to seven days) antidepressant effects in patients with treatment-resistant major depressive disorder. However, the underlying molecular mechanisms by which ketamine exerts its antidepressant effects remain unclear. Therefore, the research objective of this paper was to identify some of the molecular mechanisms that mediate the antidepressant effects of ketamine.

 

On a molecular level, it has been proposed that ketamine exerts its antidepressant effects through its metabolite, (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). Research shows that the antidepressant effects of ketamine and its metabolite in rodents requires the activation of mTORC1 kinase which controls various neuronal functions, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs).

 

In this present study, Prof. Argel Aguilar-Valles and collaborators showed that mTORC1 effectors, 4E-BP1 and 4E-BP2, are central to the antidepressant activity of ketamine. This was demonstrated through a series of physiological and behavioural assays investigating the responses to ketamine and its metabolite in mice lacking 4E-BPs in either excitatory or inhibitory neurons.

 

The results indicate that the antidepressant activity of ketamine is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1and 4E-BP2 in inhibitory neurons. In addition, the results showed that ketamine-induced hippocampal synaptic plasticity which contributes to the formation of memories depends on 4E-BP2 and, to a lesser extent, 4E-BP1.

 

The authors concluded that the “results demonstrate that brain 4E-binding proteins, and downstream initiation of mRNA translation, are a pivotal target for ketamine and its metabolite (2R,6R)-HNK. Therefore, brain 4E-BPs are appealing targets for the treatment of depressive disorders.”

 

These findings will help improve our understanding of how ketamine exerts its antidepressant effects and can potentially contribute to increasing the efficacy of using ketamine as a pharmacological treatment for depressive disorders.

 

In a brief interview conducted with Prof. Argel Aguilar-Valles, we were able to get his insight on the following questions:

 

1. What prompted you to conduct this research?

“The high rate of treatment resistance in patients with MDD and other depressive disorders is an unmet need that requires urgent research-based solutions. Treatment resistance indicates diversity in the underlying pathophysiology, but we’re still far from being able to reliably recognize different types of depression. The discovery of the antidepressant properties of sub-anesthetic doses of ketamine brought a new perspective on MDD and its treatment. However, we still don’t fully understand how ketamine exerts its powerful and rapid antidepressant effect (which contrasts with front-line treatments [like SSRIs] that can take weeks to reach their peak effect). Furthermore, ketamine is abused because of its dissociative effects at higher doses, thus a safer alternative is needed. Our ultimate goal is to understand how ketamine works and discover an alternative treatment that possesses its antidepressant properties of ketamine treatment but lacks undesirable side effects (i.e. dissociative states, hallucinations, addictive potential).”

 

2. In your opinion, what is the impact/relevance of this work in a clinical setting and in relation to wider society?

“We are still far from impacting clinical practice, but I think of our study as a stepping stone on the way to discover an alternative (or alternatives) to better treat people with depressive disorders.”

3. In your opinion, what are some of the general implications of using ketamine as a therapeutic target for MDD?

“There are some major benefits to using ketamine. Although its use in a clinical setting is restricted to patients that did not respond to two different SSRIs or SNRIs, it has provided relief to a group of patients that suffers from MDD for years and thus contributed to improving their quality of life. Also, ketamine has the ability to reduce self-harm ideation, a major cause of mortality among patients with MDD and PTSD.”

4. In your opinion, what are some future directions that could help improve our understanding as well as the efficacy of ketamine as a therapeutic target for MDD?

“Several things, we need to determine whether there are sex differences in the response to ketamine. Some pre-clinical data in mice suggests that females have a stronger response than males, but this is not always observed, and it is unclear if this is also reflected in the human population.

We identified mRNA translation, via regulation of a group of proteins called 4E-BPs, as crucial for ketamine to induce behavioural and synaptic effects. We are working to determine if this is also relevant for depressogenic contexts such as chronic stress. We are also investigating which mRNAs are being translated when ketamine is administered, and thus, which cellular responses mediate the anti-depressant effects to ketamine. The latter will be fundamental in the pursuit of a safer alternative to ketamine.”

 

To read the full version of this research manuscript please follow: https://www.nature.com/articles/s41586-020-03047-0

 

References

 

1. https://www.who.int/news-room/fact-sheets/detail/depression
2. Aguilar-Valles, A., De Gregorio, D., Matta-Camacho, E., Eslamizade, M. J., Khlaifia, A., Skaleka, A., … Sonenberg, N. (2020). Antidepressant actions of ketamine engage cell-specific translation via eIF4E. Nature, (July 2019). https://doi.org/10.1038/s41586-020-03047-0
3. Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol.

Psychiatry 47, 351–354 (2000).

4. Zarate, C. A., Jr et al. A randomized trial of an N-methyl-d-aspartate antagonist in

treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864 (2006).

5. Lapidus, K. A. et al. A randomized controlled trial of intranasal ketamine in major

depressive disorder. Biol. Psychiatry 76, 970–976 (2014).