The Neural Underpinnings of Ketamine as an Effective Therapeutic for Depression

Ketamine for depressionKetamine, once renowned as a surgical anesthetic during the Vietnam War, and more notoriously as a recreational “rave drug,” has been found to be a rapidly active and efficient antidepressant (Abdallah et al., 2015).

Exhibiting versatility as a potential treatment for different forms of depression such as bipolar, major depressive, and even refractory depression, ketamine can attenuate depressive symptoms within hours.

This makes ketamine more effective than typical antidepressants, which tend to take weeks before having a discernable effect. Additionally, these antidepressant effects can last for at least one week, even after just one administration of the drug, a remarkable phenomenon given the fact that ketamine has a half-life of only six hours (Molero et al., 2018; Andrade, 2017).

Such findings have made ketamine highly sought after for further research as a potentially groundbreaking therapeutic for depression.

A team of researchers at the University of Illinois, led by Dr. Mark Rasenick, have potentially elucidated the neural mechanism of action underlying ketamine’s antidepressant effects. After administering ketamine to nervous system glial cells derived from rats, the researchers observed that ketamine shifted the position of G-proteins, from “lipid raft” domains -where they were inactive- to non-raft domains, where they could then better facilitate communication among brain cells.

Delving further into the biochemistry of this process, this translocation better facilitates G-proteins’ production of cyclic AMP (cAMP), an important second messenger molecule implicated in a biologically essential signaling cascade. This cascade eventually culminates in increased expression of brain-derived neurotrophic factor (BDNF) (Rasenick et al., 2018).

Growing Research

Going from the biochemistry to the clinical manifestation of depression, a growing line of research has implicated BDNF expression in the symptomatology of depression. BDNF has been found to exert anti-depressant effects in the hippocampus. Moreover, sufferers of major depressive disorder (MDD) have been found to exhibit lower levels of BDNF (Lee & Kim, 2010). Therefore, these findings suggest that ketamine’s anti-depressant effect stems from elevated BDNF through inducing an initial translocation of G-proteins.

In fact, prior research by Rasenick’s team investigating the action of conventional anti-depressants such as selective serotonin reuptake inhibitors (SSRIs) on rat brain cells suggested that these compounds also induced G-protein translocation away from lipid rafts. This suggests a similar mode of action common among anti-depressants (Rasenick et al., 2018).

However, Rasenick observed that this G-protein translocation was very gradual with SSRIs, taking several days, which the team posits as the reason for why conventional anti-depressants take a long time to elicit a therapeutic effect. Conversely, in the presence of ketamine, these G-proteins commenced translocation in a matter of minutes, an intuitive, potential reason as to why ketamine is more potent and rapid-acting.

The long-lasting effect of ketamine could then be explained by the fact that, after the administration of ketamine, these G-proteins were much slower in moving back into the lipid rafts than with the SSRIs, rendering them active for longer.

In addition to G-protein translocation, this study also raises the idea that ketamine, long known to be an N-methyl-D-aspartate (NMDA) receptor antagonist, may facilitate anti-depressant effects independent of the NMDA receptor. Rasenick’s team knocked out the NMDA receptor in a mouse model, and found that ketamine still exhibited the same G-protein translocation.

As it stands, ketamine is undergoing phase III clinical trials in the U.S., where efforts are also being made to develop and administer ketamine derivatives as treatments for depression. Johnson & Johnson is leading from the front in developing Esketamine, a ketamine derivative, for administration as a nasal spray (Johnson & Johnson, 2016).

Recent research findings augur well for the potential earmarking of ketamine as an anti-depressant, as well as for the development of future analogues and derivatives of ketamine, which may prove to be even more effective treatment options for depression.

Cautious Optimism

However, ketamine’s prospects need to be treated with cautious optimism. Keep in mind that ketamine can also elicit negative side effects, particularly euphoria and hallucinations. As its use as a recreational drug shows, ketamine is a drug with definite potential for abuse (Short et al., 2018). In light of the drug epidemic afflicting millions in the U.S. today, the last thing that this country needs is the widespread misuse of yet another potent drug.

With this being said, depression is also on the rise in the U.S., with overall rates increasing by 33% since 2013. Moreover, up to 9 million insured Americans alone are affected by major depression (BCBS, 2018). Ketamine could be the crucial therapeutic to most effectively address this condition, more so than SSRIs, SNRIs and other conventional antidepressants.

However, we must not lose sight of one major guiding principle of mental health: that medications are adjuncts, not sole lines of treatment, that need to be supplemented with psychotherapy and a strong support system. Let us keep this in mind as we wait in anticipation for ketamine to be modern medicine’s ‘next big thing.’


Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2015). Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics. Annual Review of Medicine, 66(1), 509-523. doi:10.1146/annurev-med-053013-062946

Andrade, C. (2017). Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action. The Journal of Clinical Psychiatry, 78(04). doi:10.4088/jcp.17f11567

Blue Cross Blue Shield (BCBS). (2018). BLUE CROSS BLUE SHIELD, THE HEALTH OF AMERICA (pp. 1-23, Rep.). Chicago, IL: BCBS.

Johnson & Johnson, Janssen Pharmaceutical Companies. (2016, August 16). Esketamine Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration for Major Depressive Disorder with Imminent Risk for Suicide [Press release]. Retrieved from

Lee, B., & Kim, Y. (2010). The Roles of BDNF in the Pathophysiology of Major Depression and in Antidepressant Treatment. Psychiatry Investigation, 7(4), 231. doi:10.4306/pi.2010.7.4.231

Molero, P., Ramos-Quiroga, J. A., Martin-Santos, R., Calvo-Sánchez, E., Gutiérrez-Rojas, L., & Meana, J. J. (2018). Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review. CNS Drugs, 32(5), 411-420. doi:10.1007/s40263-018-0519-3

Rasenick, M. M., Wray, N., Schappi, J. M., & Singh, H. (2018). Disruption of lipid-raft localized Gαs/tubulin complexes by antidepressants: A unique feature of HDAC6 inhibitors, SSRI and tricyclic compounds. Neuropsychopharmacology, 43(7), 1481-1491. doi:10.1038/s41386-018-0016-x

Rasenick, M. M., Wray, N. H., Schappi, J. M., Singh, H., & Senese, N. B., (2018). NMDAR-independent, cAMP-dependent antidepressant actions of ketamine. Molecular Psychiatry. doi:10.1038/s41380-018-0083-8

Short, B., Fong, J., Galvez, V., Shelker, W., & Loo, C. K. (2018). Side-effects associated with ketamine use in depression: A systematic review. The Lancet Psychiatry, 5(1), 65-78. doi:10.1016/s2215-0366(17)30272-9



The Neural Underpinnings of Ketamine as an Effective Therapeutic for Depression

Racheed Mani, B.A.

Racheed Mani, B.A. is now pursuing a medical degree at the Stony Brook University School of Medicine. He previously received his bachelor’s degree in biochemistry and psychology at New York University, while also serving as a psychiatric clinical research assistant.


APA Reference
Mani, R. (2018). The Neural Underpinnings of Ketamine as an Effective Therapeutic for Depression. Psych Central. Retrieved on September 19, 2020, from


Scientifically Reviewed
Last updated: 1 Aug 2018
Last reviewed: By John M. Grohol, Psy.D. on 1 Aug 2018
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