How Do Ketamine and Esketamine Work as Fast-Acting Antidepressants?

What you need to know

Ketamine and esketamine are fast-acting antidepressants that work differently from traditional antidepressants
They rapidly relieve depression symptoms by targeting glutamate receptors in the brain
Esketamine nasal spray was approved for treatment-resistant depression in 2019
While effective, these drugs can have side effects and require medical supervision

How ketamine works as an antidepressant

Ketamine was originally developed as an anesthetic, but researchers discovered it could rapidly relieve depression symptoms. Unlike traditional antidepressants that target serotonin, norepinephrine or dopamine, ketamine works on the glutamate system in the brain.

Specifically, ketamine blocks a type of glutamate receptor called the NMDA receptor. This blocking action is thought to trigger a cascade of effects that ultimately lead to rapid antidepressant benefits:

Ketamine blocks NMDA receptors on certain inhibitory neurons in the brain. This reduces the activity of these inhibitory neurons.
With less inhibition, excitatory glutamate signaling increases in areas of the brain involved in mood regulation.
This burst of glutamate activates proteins involved in forming new connections between neurons.
Over time, this leads to increased neuroplasticity - the brain’s ability to form new neural connections.
The boost in neuroplasticity is thought to help “rewire” depression-related circuits in the brain.

This process allows ketamine to produce antidepressant effects within hours or days, compared to weeks or months for traditional antidepressants. The effects can also last for days or weeks after a single dose.

Ketamine dosing and administration

For depression treatment, ketamine is typically given at a much lower dose than used for anesthesia. It can be administered in several ways:

Intravenous (IV) infusion
Intramuscular injection
Intranasal spray
Oral tablets

The most common method in clinical practice is IV infusion. A typical dose is 0.5 mg/kg infused over 40 minutes.

Ketamine has a complex metabolism in the body. It is broken down in the liver to form several metabolites. Some of these metabolites, like norketamine, may contribute to the antidepressant effects.

Development of esketamine

Ketamine exists as two mirror-image forms called enantiomers - R-ketamine and S-ketamine (also called esketamine).

Researchers found that esketamine binds more strongly to NMDA receptors than R-ketamine. This led to the development of esketamine as a standalone antidepressant medication.

In 2019, the FDA approved an esketamine nasal spray (brand name Spravato) for treatment-resistant depression. This was a significant milestone as the first novel antidepressant mechanism approved in decades.

How esketamine is used

Esketamine nasal spray is used along with an oral antidepressant for treatment-resistant depression. Key aspects of its use include:

It is only administered in a healthcare setting under medical supervision.
The starting dose is 56 mg twice weekly for 4 weeks.
After 4 weeks, the dose may be increased to 84 mg if needed.
Treatment is then reduced to once weekly for 4 weeks, then once every 1-2 weeks as maintenance.
Patients are monitored for at least 2 hours after each dose due to potential side effects.

The nasal spray allows for easier administration compared to IV ketamine. However, absorption can be variable between individuals.

Pharmacology of esketamine

When given as a nasal spray, about 48% of esketamine is absorbed rapidly through the nasal mucosa. The rest is either swallowed or remains in the nasal cavity to be absorbed more slowly.

Esketamine reaches peak levels in the blood within 20-40 minutes after dosing. It is then metabolized in the liver, primarily by enzymes called CYP2B6 and CYP3A4.

The main metabolites are:

Noresketamine - has similar effects to esketamine but with less psychoactive effects
Hydroxynorketamine - may contribute to antidepressant effects through different mechanisms

These metabolites are then eliminated mostly through urine.

Mechanism of action

Like ketamine, esketamine is thought to work primarily by blocking NMDA glutamate receptors. This triggers a cascade of effects including:

Increased glutamate release
Activation of AMPA glutamate receptors
Enhanced signaling of growth factors like BDNF (brain-derived neurotrophic factor)
Increased protein synthesis and synapse formation

This ultimately leads to enhanced neuroplasticity in brain regions involved in mood regulation. However, some research suggests the metabolites of esketamine may also contribute to antidepressant effects through other mechanisms.

Effectiveness for depression

Clinical trials have shown esketamine nasal spray to be effective for treatment-resistant depression when used with an oral antidepressant. Key findings include:

Rapid improvement in depression symptoms, often within 24 hours
Sustained improvement with continued treatment
Effective in reducing suicidal thoughts in patients at imminent risk

However, more research is still needed on long-term efficacy and which patients are most likely to benefit.

Side effects and safety considerations

Common side effects of esketamine include:

Dissociation (feeling disconnected from your surroundings)
Dizziness
Nausea
Sedation
Increased blood pressure

Most side effects occur shortly after dosing and resolve within 1-2 hours. However, patients are monitored for at least 2 hours after each dose as a precaution.

Other safety considerations include:

Potential for abuse - esketamine is a controlled substance due to its dissociative effects
Cognitive impairment - may affect attention, judgment, and thinking
Bladder problems - long-term use may cause urinary tract issues
Suicidal thoughts - may increase in some patients, especially early in treatment

Due to these risks, esketamine is only available through a restricted distribution system. It cannot be dispensed directly to patients for home use.

Sex differences in response

Some research has found differences in how males and females respond to ketamine and esketamine:

In animal studies, females tend to be more sensitive to low doses of ketamine
Human studies have had mixed results, with some showing longer-lasting effects in males
Females may have higher rates of nausea and headache as side effects

However, more research is needed to fully understand sex differences in response and determine if dosing should be adjusted based on sex.

Conclusions

Ketamine and esketamine represent a novel, rapid-acting approach to treating depression
They work through glutamate receptors to quickly enhance neuroplasticity in the brain
While effective for many patients, they require careful medical supervision due to side effects
More research is still needed on long-term efficacy, safety, and optimal use

Ketamine and esketamine offer new hope for patients with treatment-resistant depression. However, they are powerful medications that should only be used under close medical supervision. Ongoing research aims to further optimize their use and potentially develop new rapid-acting antidepressants with improved safety profiles.