Ketamine’s Mechanism of Action in Treating MDD

Ketamine’s mechanism of action and sustained effects on decreasing symptoms of major depressive disorder (MDD) and suicidal thinking are powerful. But, there is an incomplete understanding and lack of consensus on ketamine’s mechanism. This is partly due to our early understanding of depression and its biological underpinnings.

Ketamine is FDA approved as an anesthetic and acts as a selective NMDA receptor antagonist on GABAergic interneurons (Note: NMDARs are receptors for the excitatory neurotransmitter glutamate; GABA is an inhibitory neurotransmitter). This resulting disinhibition leads to a rapid release of glutamate. The downstream effects of this release include activation of more glutamate receptors, including AMPA, an increase in brain-derived neurotrophic factor (BDNF) and activation of signaling pathways to increase synaptogenesis, the process by which the brain can grow, repair, and form new connections.1

Ketamine’s mechanism of affecting NMDARs has been highlighted as the mechanism of action responsible for its anti-depressive effects. Ketamine has two main enantiomers (mirror-image subcomponents): R-ketamine and S-ketamine. S-ketamine has approximately four times stronger potency as an NMDAR antagonist compared to R-Ketamine but in recent rodent studies was less effective at decreasing depressive symptoms.2  Studies of medications are often conducted in rodents rather than humans because of ethical and safety considerations, as well as the ability to study their brains in a way that would not be possible with human subjects. Other NMDAR antagonists used to treat depression have also not shown the same efficacy, although this may be a function of dose studied.3

There are several other possible mechanisms of action to explain ketamine’s effects; AMPA receptors, plasticity, inflammation, and the gut-brain axis.

Ketamine’s mechanism of action has been shown to increase AMPA receptor activation in the medial prefrontal cortex (mPFC) and hippocampus in animal models 4, areas of learning, memory, emotion, and higher-level thinking. When these receptors are blocked in animal models, the effects of ketamine on depressive symptoms disappear.5 These brain regions are known to have reductions in AMPA receptors in humans with depression (based on post-mortem analysis). Together, this evidence gives this mechanism of action strong support that requires further investigation in humans.6 It is important to recognize the limitation of rodent studies and rodent models of depression and to be careful not to immediately generalize these results to human use.

People with chronic Major Depressive Disorder have structural changes in the hippocampus and prefrontal cortex, leading to atrophy and decreased the quality of connections. Relief of symptoms from ketamine or other antidepressants correlates with reversal of these structural changes.7 BDNF  is a protein that that is very important for synaptogenesis within the hippocampus and prefrontal cortex. Ketamine has shown an acute increase in BDNF in these regions in animal models, whereas more traditional antidepressants take weeks to increase BDNF levels.8

Another plasticity mechanism is the mTOR signaling pathway, which increases protein synthesis in the neuronal synapses.  When rapamycin (selectively inhibits mTOR activation) is administered prior to a ketamine treatment for depression, the effects of synaptogenesis and improved depressive symptoms will be blocked.9 The mTOR signaling pathway is known to be directly activated with traditional antidepressants.10

Major Depressive Disorder and other mood disorders are correlated with higher levels of inflammation. Likewise, a high body mass index (BMI) is also correlated with higher levels of inflammation in the peripheral and central nervous systems. Perhaps not coincidentally, one patient characteristic that has been correlated with improved antidepressant response to ketamine is higher BMI.   Ketamine was also recently shown to decrease the adipokine resistin (a strong pro-inflammatory) in plasma levels of individuals post-infusion for depression or bipolar disorder, as well as pro-inflammatory cytokines such as IL-6 .12 These two pieces of data taken together hint at ketamine’s ability to decrease inflammation is correlated with a decrease in depressive symptoms.

The microbiota of people with MDD are altered and are thought to play a part in the pathogenesis of depression.13 Butyricimonas is a gut microbe that has strong anti-inflammatory properties and its deficiency has been linked to MDD in humans.  A recent animal study found that ketamine  treatment significantly increased butyricimonas bacteria in the gut and was correlated to improvement in depressive-like symptoms.14

As outlined above, ketamine’s mechanism in the body and brain are diverse and complex.  It is perhaps this breadth of mechanism that partially explains ketamine’s unique properties.  The results of ketamine infusion to treat major depressive disorder and related comorbidities are compelling. Research is advancing rapidly to understand its mechanism to develop more precise medication for the future treatment of major depressive disorder and other mood disorders, representing a hopeful frontier.

Tirzah M. VanDamme, MS

Tirzah spent almost a decade in the U.S. Army as a medical evacuation pilot. As she saw others struggle and struggled herself to cope with all of the stresses of the military, she became interested in the science of the brain and ways to optimize the brain to improve performance, leading her to pursue a master’s degree in neuroscience from Uniformed Services University of the Health Sciences. Tirzah is currently pursuing an MBA at Harvard Business School.