Can Ketamine Improve Treatment-Resistant Depression?

(Posted on Friday, May 17, 2024)

KEY POINTS

• A new study probes ketamine’s diverse brain impacts for depression treatment insights.
• Ketamine shows complex neural patterns, affecting inhibitory and excitatory brain circuits.
• Understanding ketamine’s varied responses is crucial for developing personalized depression therapies.

Ketamine, a strong anesthetic, is growing increasingly popular for its potential in treating treatment-resistant depression. The effectiveness, however, is varied with only some patients feeling the benefits. A recent study led by Flora Moujaes at Yale University investigates ketamine’s effects on brain activity and behavior in healthy individuals, revealing complex neural patterns. Understanding these nuances could lead to more targeted treatments for depression, offering hope for those who have not responded to conventional antidepressants.

Ketamine is an NMDA (N-methyl-D-aspartate) receptor antagonist, a drug that binds to and blocks the NMDA receptor, which is a type of glutamate receptor in the brain. Ketamine prevents the binding of the excitatory neurotransmitter glutamate to the NMDA receptor, thereby reducing the influx of calcium into nerve cells. This can have various effects, relieving pain, working as an anesthetic, or impairing memory.

Ketamine was developed in the 1960s to be used as a battlefield anesthetic in the Vietnam War as well as in health care settings. It was historically used in highly regulated and supervised health care facilities but its usage has changed significantly since then.

How Ketamine Is Used Today

Ketamine is approved by the United States Food and Drug Administration as an anesthetic and is widely used for short, painful procedures that require immobilization. It’s often used for sedation in emergency departments, operating rooms, wound care clinics, and ambulances.

While ketamine has only been approved as an anesthetic, it is also used “off-label” for other purposes. Because it has pain-relieving effects similar to morphine or fentanyl, it is used for pain management, including cancer pain and other chronic illnesses.

Ketamine is also used recreationally for its dissociative and hallucinogenic effects, often in party or club settings, but this has significant dangers and health risks, including respiratory issues, psychosis, memory loss, and the potential for overdose, especially when combined with other substances like alcohol or opioids.

An interesting loophole in the United States Food and Drug Administration’s prescription drug-advertising regulations allows drugs to be promoted online and in social media without being held to any standard. That means ketamine is now advertised as a treatment for various psychiatric illnesses including depression, anxiety, and post-traumatic stress disorder, as well as Lyme disease, alcoholism, and opioid addiction.

Ketamine as Therapy

Despite limited approval for legal uses, there are promising signs of ketamine helping those who suffer from treatment-resistant depression. Treatment-resistant depression is a type of major depressive disorder in which a person’s depression symptoms do not improve after trying at least two different first-line antidepressant medications of adequate dosage and duration (usually six to eight weeks). It is relatively common, affecting up to 30% of people diagnosed with major depressive disorder. People with treatment-resistant depression often have more severe, frequent, and longer-lasting depressive episodes and it often requires trying multiple different medication strategies to find an effective approach.

Previous studies have found evidence of ketamine as a potentially effective treatment for depression but the results have varied widely. Few studies have observed the variations in ketamine-induced symptoms and why ketamine has positive effects for some but not for others. The recent study led by Flora Moujaes of the Department of Psychiatry at the Yale University School of Medicine and published in eLife investigates whether individuals show significant differences in brain activity and behavior in response to ketamine.

Forty healthy individuals were first given a placebo drug and then ketamine. Brain imaging was done throughout the experiment. Because ketamine is a molecule that acts at the same target in every human brain (the NMDA receptor), it would make sense for it to have one clear pattern of brain activity, or a single component that best explains the variation in data. Using principal component analysis, however, the study finds that ketamine results in multiple bi-directional neural principal components.

This may be due to the influence it has between different parts of the brain; for example, the connection between two excitatory parts of the brain or between an excitatory part and an inhibitory part. It may also target specific types of cells in the brain more strongly based on their receptor makeup. Or it could be affecting various smaller circuits within the brain. These different patterns might be influenced by factors like how often the brain’s NMDA networks are used, genetic differences in the receptors, and even how someone sleeps.

To compare whether brain variability between individuals is due to ketamine in particular or whether it is common among other drugs with anti-depressive effects, the researchers looked at the effects of psilocybin and LSD (lysergic acid diethylamide). Ketamine has higher individual variability and seems to have more complex effects on the brain than LSD and psilocybin. This may be because psilocybin and LSD work mainly by activating a specific type of receptor that is found on fewer types of brain cells compared to the receptors that ketamine effects.

Another reason for ketamine’s complexity is that it has both inhibitory (calming) and excitatory (stimulating) effects on the brain. Psilocybin and LSD, however, mainly have stimulating effects. Ketamine indirectly increases brain activity by calming certain types of cells called interneurons. So, while psilocybin and LSD primarily stimulate the brain in a more straightforward way, ketamine’s effects are more varied because it affects many different brain circuits and has both calming and stimulating effects.

Limitations and Future Directions

The neural measures of this study were only collected during ketamine’s peak effects, potentially missing important dynamics during the post-infusion period when antidepressant effects are observed. Additionally, long-term effects of ketamine were not included in this study and are often missing from clinical studies. Future studies may benefit from collecting additional follow-up scans to capture longer-term effects. Importantly, larger sample sizes are needed to fully unpack the variation in neural effects, especially regarding bidirectional axes of variation represented by different principal components.

This research holds the potential to advance understandings of treatment-resistant depression and revolutionize treatment approaches, creating personalized treatment strategies that consider genetic variations, neural circuitry, and demographic characteristics. Understanding the timing and duration of ketamine’s effects could also help optimize treatment protocols for treatment-resistant depression by refining dosing schedules.

One of the goals of psychiatric research is to predict treatment response. Because ketamine has such varied responses, developing effective treatment is a significant challenge. Examining the variability in individual behavioral and neural response to ketamine provides the potential to generate predictions of how people may respond to it, providing hope for the millions suffering from treatment-resistant depression.

Read the article online on Psychology Today.