Nasal Esketamine vs. Intravenous (IV) Ketamine

In March, 2019, esketamine (also known as S-ketamine) received FDA approval in the form of a nasal spray in conjunction with an oral antidepressant for patients with treatment resistant depression (TRD) who have failed two antidepressant medications from two different pharmacological classes.  Many patients are asking what the difference is between esketamine and ketamine.

Ketamine has been an FDA approved anesthetic for decades and is the anesthesia of choice for children because of its excellent safety profile (no respiratory effects).  Research demonstrates that ketamine is also an effective treatment for TRD when used intravenously (IV) in low doses (approximately 1/10th of anesthetic doses).  More recently, research also demonstrates efficacy for anxiety, PTSD, chronic pain, fibromyalgia, and more.  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.

Esketamine is a molecule taken from ketamine’s racemic mixture (basically 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 indicated use of nasal esketamine for TRD.

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.  For instance, transcranial magnetic stimulation (TMS) was FDA- indicated for TRD as early as 2008. It was not until seven years later, circa 2015, that TMS became a covered benefit on most insurance plans.  TMS being a covered benefit does not equate with insurance authorization for TMS coverage or authorization with the same FDA-indication. TMS is FDA-indicated for depressed patients who have failed one antidepressant medication of adequate dose and duration. Most insurance companies, however, require that patients have failed multiple antidepressant trials, with augmentation strategies and therapy, before they will authorize payment.

Currently cited costs of esketamine are $590 for the 56 mg dose and $885 for the 84 mg dose. It is yet to be seen whether or not insurance companies will cover these costs or what clinical guidelines will be required for authorization of coverage.

Both ketamine and esketamine can be delivered intravenously, intramuscularly, or intranasally.  However, intravenous delivery is the most effective when it comes to the absorption, accuracy, and efficacy of the dose. 

IV ketamine is administered at a slow, controlled rate throughout a typical 40-minute treatment.  The dose is calculated according to a patient’s weight and individually adjusted according to the patient’s tolerability.  A course of treatment includes 6-8 infusions over a 3-4 week period and the patient must have transportation arrangements. Most patients will achieve response or remission after 3-4 weeks and will remain healthy, not needing any IV ketamine boosters, for 3-4 months.

The recent FDA approval of nasal esketamine is only available at preapproved healthcare facilities per FDA regulations.  This is being done as an effort to reduce abuse and misuse of the drug.  The currently recommended doses are either 56 mg or 84 mg and a 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 he/she self-administers 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.

Potential side effects for both drugs include sedation and mild dissociation.  On awakening from an IV infusion, patients may experience blurred vision, feelings of lightness, and, rarely, headache or nausea (prevented by including an iv anti-nausea medication with the infusion).  In addition to the same side effects from IV administration, intranasal doses may also cause vertigo, decreased sensitivity, anxiety, and vomiting.  Regardless of delivery method, patients often experience results within days or even hours. 

IV ketamine has a 70-80% success rate in treating TRD and has been used in the clinical psychiatric community since 2010, providing 9 years of real world experience. It is likely that esketamine will also be effective because it is a molecular part of ketamine itself. However, we currently have no real world clinical experience regarding actual dosing, efficacy, side effects or treatment protocols outside of the FDA-approval clinical trials that had stringent selective criteria for patients to participate.

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.  Most antidepressants operate via modulating serotonin, norepinephrine and dopamine.  In contrast, ketamine/esketamine modulates glutamate NMDA receptors resulting in an increased production of neurotrophic factors (particularly BDNF) that repair damaged neurons and improve neuronal connectivity within the brain.  It is very exciting for psychiatry to have a novel treatment to offer patients suffering from TRD.

3 responses to “Nasal Esketamine vs. Intravenous (IV) Ketamine

  • Sofro de depressão seria onde encontrar como faço poderiam me ajudar Não aguento mais ficar deste jeito

  • Greg McCracken

    9 months ago

    The only advantage to esketamine is that it does not require an IV. That’s it. You still have to go to a clinic to get it, it costs a lot of money, and you can’t tailor the dosage to what the patient needs. You only have 2 dosage choices, high and low.

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