5 Ways Ketamine Works on the Brain to Reduce Depression

By: Jayson Tripp, MD


Ketamine is a drug that was originally developed as an anesthetic and painkiller. But in more recent years, medical research has found that it can rapidly reduce the symptoms of clinical depression, especially for people who have not been successful with conventional drug therapy.

In fact, studies show that up to about 70% of patients experience significant symptom relief with ketamine, while only around 30–40% respond to traditional antidepressant medications. But how and why does ketamine work so quickly and effectively for so many people? In this blog, we will explore five ways ketamine affects the brain to produce a rapid antidepressant effect for severe depression.

1. Ketamine Activates Glutamate Neurotransmission in the Prefrontal Cortex

One of the reasons researchers believe ketamine to be so much more effective than traditional medications is because it activates glutamate neurotransmission in the prefrontal cortex, the part of the brain responsible for personality, impulse control, focus, and communicating with other parts of the brain that process emotion.

Scientists have found that the glutamate neurological pathways respond much more rapidly to medications than the serotonin and dopamine pathways, which are targeted by traditional antidepressants like SSRIs and MAOIs. Therefore, ketamine helps improve the brain’s processing abilities related to personality, mood and impulse control.

2. Ketamine Targets the NMDA Receptor

Ketamine also targets the area of the nervous system known as the N-methyl-D-aspartate (NMDA) receptor. This receptor is a type of glutamate neurotransmitter that is vital to nerve cell communication and memory.

For whatever reason, the NMDA seems to function poorly in people with depression. Scientists have noticed an increase in glutamatergic excitotoxic activity — in other words, damaged neurons — associated with the NMDA receptor in patients with major depression. Luckily, ketamine helps improve the way the NMDA receptor functions by stopping the damage to certain circuits of the brain.

3. Ketamine Targets the Lateral Habenula

In attempting to learn more about why ketamine affects the NMDA receptor, researchers found that the drug also improves the function of the lateral habenula. The lateral habenula is an important part of emotional processing in the brain. It is what fires when we experience setbacks or disappointment, and blocks dopamine, the chemical released in the brain that produces feelings of pleasure.

One study showed that in depressed patients, the lateral habenula may fire too much, causing increased feelings of disappointment and hopelessness. Although scientists still don’t know why the lateral habenula does not function as well in depressed patients, they do know that ketamine helps to regulate and improve function in this area of the brain.

4. Ketamine Regrows Connections in the Brain

The final theory that researchers have on why and how ketamine reduces depression symptoms is that it prompts the growth of new connections between nerve cells in the brain that relate to mood and emotion.

In one study, patients who were given ketamine showed increased brain activity associated with the regrowth of neurons in the areas of the brain that are associated with depression. Because the effects can happen within hours instead of months, ketamine has emerged as one of the most exciting advancements in modern treatment for mental health.

5. Ketamine Resets the Brain

While ketamine is in the bloodstream, it essentially shuts off communication between the brain and the body, slowing the function of the nervous system. This could be the reason glutamate neurotransmitters and other areas of the brain show improvement after the drug has left the patient’s system. Ketamine shuts down those areas of the brain, and when they are turned on again, they are rebooted and functioning more smoothly.

When asked about her experience with ketamine, a patient from Serenity Mental Health Centers said, “It felt like someone turned my brain back on—that’s the only way can describe it”, demonstrating how well ketamine acts to “reboot” the brain to a better functional state.

Research shows that ketamine can improve brain function in a few different ways, and it can target areas of the brain that other antidepressants cannot. Thomas Insel, MD, director of the National Institute of Mental Health says, “Recent data suggest that ketamine, given intravenously, might be the most important breakthrough in antidepressant treatment in decades.”

Scientists and doctors continue to study the amazing effects of this drug to learn more about how it affects brain function to reduce the symptoms of severe depression. Hopefully, their findings will lead to the development of new antidepressants that can treat the symptoms of depression more quickly, effectively, and with little side effects.

If you would like to learn more about ketamine therapy, contact Serenity Mental Health Centers and schedule an appointment for a consultation with a psychiatrist.

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*All information subject to change. Images may contain models. Individual results are not guaranteed and may vary.