Ketamine Vs Esketamine

Amidst the growing mental health crisis, a pressing need for innovative and effective treatments has emerged. The prevalence of conditions like major depressive disorder has escalated in the past couple of decades and has spiked dramatically in the wake of the pandemic, revealing the limitations of first-line depression treatments like SSRI medications and other traditional antidepressant drugs. Once heralded as the cornerstone of depression treatment, these medications are now being scrutinized for their varying degrees of effectiveness, their significant profile of side effects, and the persisting challenges they present for individuals with treatment-resistant depression. As the quest for improved mental health outcomes gains momentum, ketamine and esketamine treatments have become powerful tools in the fight against treatment-resistant depression, bipolar disorder, and other mood disorders and mental health conditions.

Ketamine and esketamine are both used to treat individuals diagnosed with depression who have not had success with traditional antidepressant medications. In this article, we’ll dissect the differences between ketamine and esketamine, shedding light on their distinct attributes as they offer new rays of hope for those grappling with the weight of treatment-resistant depression.

What Is Ketamine?

Ketamine is an FDA-approved anesthetic medication that has been used in hospital settings for decades. Initially developed in the 1960s, ketamine, and its derivatives are unique medications because, unlike many other anesthetics, ketamine does not slow down the body’s central nervous system (CNS). The early 2000s marked a turning point for researchers exploring ketamine’s potential beyond its anesthetic properties. Initial studies investigating its effects on mood disorders observed a rapid and profound alleviation of depressive symptoms, even in individuals who had not responded well to traditional antidepressants. These findings sparked a surge of interest within the scientific and medical communities, leading to a series of controlled trials that further highlighted ketamine’s astonishing ability to treat depression quickly and effectively.

IV Ketamine’s Mechanism of Action

By targeting a different neurotransmitter system than traditional antidepressants, ketamine treatments target glutamate, a neurotransmitter involved in synaptic plasticity and mood regulation. This stands in contrast to antidepressant drugs like selective serotonin reuptake inhibitors (SSRIs), which primarily influence serotonin levels.

IV Ketamine Administration

Ketamine treatments usually take place in the form of IV ketamine infusions. Research demonstrates that ketamine is effective in treating depression even when used in low doses; approximately 1/10th of anesthetic doses. IV ketamine is administered at a slow, controlled rate throughout the 40-minute treatment sessions. The dose is calculated according to a patient’s weight and individually adjusted according to the patient’s tolerability. A course of treatment typically includes 6-8 infusions over a 3-4 week period. Most patients will achieve response or remission after 3-4 weeks of the ketamine infusion therapy and will remain healthy and not need any IV ketamine boosters for 3-4 months.

IV Ketamine Success Rates and Efficacy

IV ketamine has a 70-80% success rate in treating treatment-resistant depression and has been used in the clinical psychiatric community since 2010, providing over a decade of real-world experience. One of the major advantages of ketamine and esketamine treatments over traditional antidepressants is the speed at which these compounds can alleviate symptoms of depression. Ketamine can lead to a rapid reduction in depressive symptoms, sometimes within a few hours of treatment. This makes ketamine particularly important for severe cases of depression where suicidal ideation is present. More recently, research has also demonstrated that intravenous ketamine may effectively treat anxiety, post-traumatic stress disorder (PTSD), chronic pain, fibromyalgia, and more.

IV Ketamine and Insurance Coverage

However, IV ketamine remains “off-label” for these purposes because it is not FDA-indicated for use in treating these diagnoses. In fact, the FDA will most likely never approve ketamine for indications other than anesthesia because the patent for ketamine expired long ago. Without a patent, pharmaceutical companies are unlikely to invest in the costly clinical trials necessary to meet the FDA’s requirements for approval, simply because they cannot monetize the drug.

What Is Esketamine (Spravato)?

Esketamine (marketed under the brand name Spravato) is a derivative of ketamine that received FDA approval in the form of a nasal spray medication. Like regular ketamine, esketamine nasal spray is used for patients with treatment-resistant depression (TRD) who were unable to find symptom remission from at least two antidepressant medications from two different pharmacological classes.

Spravato’s Mechanism of Action

Just like ketamine, Spravato’s mechanism of action distinguishes it from conventional antidepressant medications. While traditional antidepressants primarily target neurotransmitters like serotonin, esketamine acts on the glutamate neurotransmitter system. Glutamate plays a pivotal role in synaptic plasticity and mood regulation, and its modulation through esketamine is believed to contribute to the rapid and profound antidepressant effects observed in some individuals.

Spravato Administration

Unlike oral antidepressant pills or intravenous racemic ketamine, Spravato is administered through a nasal spray. The nasal spray delivery system used in esketamine treatment allows for efficient absorption into the bloodstream, enabling rapid onset of action and minimizing the need for complex procedures or hospitalization.

Similar to IV ketamine treatments, Spravtato treatment typically involves a controlled and monitored process. Patients receive the nasal spray under the supervision of a healthcare professional, and they are required to remain under observation for a specified period afterward due to the potential for side effects.

The recommended treatment course is for administration twice weekly for the first four weeks, weekly for the next four weeks, and then weekly or bi-weekly thereafter. A trained professional must supervise the patient while they self-administer the nasal spray to each nostril. Following the dose, the patient must remain at the facility for two hours of observation and must have transportation arrangements. The treatment schedule initially involves a series of doses over a few weeks, followed by maintenance doses as determined by the treating physician.

Spravato Success Rates and Efficacy

Clinical trials have shown that esketamine can lead to a rapid reduction in depressive symptoms, often within hours or days, as opposed to the weeks required by many traditional antidepressants. As mentioned above, Spravato has the ability to assuage depression symptoms quickly, which can be particularly important for severe cases of depression where suicidal ideation is present.

Spravato and Insurance Coverage

Esketamine is a molecule taken from ketamine’s racemic mixture (two mirror-image molecules which spin in different directions). As it is an altered form of ketamine, esketamine could be newly patented. As a result, corporate dollars were invested in clinical trials that led to the current FDA’s indicated use of nasal esketamine for treatment-resistant depression.

FDA approval is a precursor for an insurance company to offer coverage. However, FDA approval and insurance coverage are not simultaneously guaranteed, or guaranteed with the same clinical guidelines. Most insurance companies require that patients have failed multiple antidepressant trials, with augmentation strategies and therapy, before they will authorize payment.

Perhaps the most significant aspect of the recent FDA approval for esketamine is that it is the first antidepressant approved with a novel mechanism of action since the introduction of Prozac in 1987. As mentioned, in contrast to traditional antidepressants, ketamine and esketamine modulate glutamate NMDA receptors resulting in an increased production of neurotrophic factors (particularly BDNF) that repair damaged neurons and improve neuronal connectivity within the brain. According to John Hopkins Medicine, esketamine is the only drug other than lithium that has been proven in studies to decrease suicidal thoughts. 

Side Effects of Esketamine and Ketamine

As with any medication, esketamine and ketamine are associated with potential side effects. Side effects tend to peak at around 40 minutes and wear off within two hours after a treatment session ends. The most intense side effects typically occur during the first two treatments and lessen after that. 

Side effects of esketamine may include: 

  • Nausea
  • Headache
  • Drowsiness
  • Increased blood pressure
  • Feeling drunk
  • Blurred vision
  • Feeling of lightness
  • Mild disassociation
  • Vertigo
  • Decreased sensitivity
  • Anxiety
  • Hallucinations, in rare occurrences

Side effects of ketamine may include:

  • Rapid heartbeat
  • Headache
  • Nausea, which can be prevented by including an IV anti-nausea medication with the infusion  
  • High blood pressure
  • Blurred vision
  • Feeling of lightness
  • Spontaneously making sounds or speaking
  • Drowsiness
  • Mild disassociation
  • Delirium
  • Hallucinations

Which Treatment is Right for You?

Determining whether IV ketamine or esketamine (Spravato) is the right treatment for you requires a consultation with a qualified medical professional, and an assessment of your specific medical history, current health status, and treatment goals. Both IV ketamine and esketamine have shown promise in addressing treatment-resistant depression, but they have distinct characteristics that might influence the decision.

Here are a few factors to consider when discussing the choice between IV ketamine and esketamine with your healthcare provider:

Medical History and Health Status

Your medical history, including any pre-existing health conditions, allergies, and medications you are currently taking, will play a significant role in determining which treatment is safer and more suitable for you. Your doctor will need to evaluate if there are any potential contraindications or risks associated with either treatment option.

Treatment Setting and Frequency

IV ketamine is often administered in a medical clinic under the supervision of healthcare professionals, typically through a series of sessions over several weeks. Esketamine (Spravato) is administered as a nasal spray and can be taken under medical supervision at a healthcare facility or at home, depending on your doctor’s recommendation. The frequency and duration of treatment sessions can differ between the two options.

Convenience and Accessibility

Esketamine’s nasal spray administration might offer more convenience for some individuals, as it doesn’t require intravenous infusion and can be administered more flexibly. However, the decision between convenience and the potential benefits of IV administration should be made in consultation with your healthcare provider.

Response and Tolerance

Responses to IV ketamine and esketamine can vary among individuals. Some people might respond better to one treatment than the other. Your doctor may monitor your response and any side effects during the initial sessions to guide treatment decisions.

In general, Spravato treatment is more intense than IV ketamine treatment, but both IV ketamine and esketamine are associated with potential side effects, including dissociation, dizziness, and other reactions. Your healthcare provider will discuss the potential side effects, how they are managed, and what level of supervision is needed during and after each session.

Cost and Insurance Coverage

Because IV ketamine is not an FDA-approved treatment, it is almost never covered by insurance. Spravato, on the other hand, usually is covered by insurance.


In the end, the decision between IV ketamine and esketamine should be based on a comprehensive evaluation by a qualified medical professional who understands your unique circumstances. It’s essential to have an open and honest conversation with your doctor about your symptoms, preferences, and concerns. Together, you can make an informed decision that aligns with your treatment goals and optimizes your chances for a positive outcome in managing treatment-resistant depression.

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