On March 5, 2019, the FDA approved esketamine CIII nasal spray as a “new option” for treatment-resistant depression under the brand name SPRAVATO®. This led many to ask a question that is as common today in 2022 as it was 3 years ago; “what is esketamine?” Equally common is individuals’ desire to understand the differences between ketamine vs. esketamine and what that means about available depression treatments.

Esketamine AKA “S-ketamine” is literally one part of ketamine — which has a 52+ year history as a safe, effective, fast-acting anesthetic and analgesic used in human and veterinary medicine. Ketamine was approved by the FDA in 1970. For the last 22 years, IV infusions of ketamine have become increasingly common as one of the fastest-acting and most effective ways to treat depression, suicidal ideation, and other mental health conditions. Since IV ketamine is an old, generic drug with an expired patent, pharmaceutical companies sought to create a variation of it that could be patented for profitability. Enter stage left esketamine the ketamine nasal spray, aka Spravato. While the two are very much the same substance, there are some significant differences, primarily in the route of administration (ROA), which means the way the medicine is taken. Understanding how they differ as depression treatment options is crucial. Here are some of the FAQs to help you understand the differences of ketamine vs. esketamine.

Ketamine vs. Esketamine

When comparing ketamine vs. esketamine, it’s important to note that esketamine is essentially one part of ketamine. Ketamine is composed of two mirror-image molecules that exist together but spin in different directions—this is called a racemic mixture. Ketamine is composed of two molecules known as R-ketamine and S-ketamine. Imagine your hands, mirror images of one another. The same, but different. When a racemic mixture is separated, each molecule on its own is called an enantiomer. Therefore, as the S-enantiomer of ketamine, esketamine (s-ketamine) is literally one-half of the molecular compound ketamine.

Do Esketamine and Ketamine Work the Same Way?

Although scientists are still studying exactly how and why these drugs stimulate relief from depressive symptoms so quickly and effectively, most researchers believe both drugs work as N-methyl-D-aspartate (NMDA) receptors. Both medications restore the brain’s proper levels of the most prevalent neurotransmitter glutamate (occurs in 90%+ of the brain), which in turn re-establishes the correct balance of other neurotransmitters required for a healthy, well-functioning brain. Many other neurochemical processes occur when s-ketamine, r-ketamine, or ketamine enter the bloodstream.

While both ketamine and SPRAVATO® for depression act similarly on a molecular level, the route of administration (ROA) is one of the biggest differences between the two. Ketamine Infusion Therapy delivers a precisely controlled dose of ketamine directly into the bloodstream through an IV. This delivery mechanism ensures 100% bioavailability – that all of the drug enters the bloodstream with zero metabolites. Metabolites are substances that are created when the body breaks down other substances, such as food or medicines, and they affect the way the body responds to the original substance. Spravato is taken intranasally, through the nose as a spray. The intranasal ROA has a range of 25-50% bioavailability.

Some providers prescribe generic ketamine to be taken at home as a ketamine nasal spray. This is no more effective than Spravato, about half as effective as IV ketamine infusions, and not considered to be a safe practice. It is not advisable.

SPRAVATO® vs. Infusion: Which is More Effective?

Because SPRAVATO® is a new treatment, and the research has been paid for by the manufacturer and owner of the patent, there are no studies specifically comparing SPRAVATO® vs. Infusions. While both options can be effective when other treatments have failed, and both can produce rapid results, ketamine has proven to be faster acting and more effective than SPRAVATO® in clinical research and real-world application. In most studies, Spravato shows around 40% efficacy while IV Ketamine shows around 70% efficacy. At Ketam, IV83% of the time. The two-fold increase in efficacy of ketamine infusions vs esketamine is not likely due to differences in the chemical composition of the drugs, but more so to the ROA.

Still, Spravato can be a useful tool in the fight against depression. Ketamine is an out-of-pocket procedure. KCLA offers interest-free financing and works to keep prices low and some patients are still averse to non-insurance-based treatment options. While the co-pays and deductible limits associated with Spravato vary widely from plan to plan and in some cases may be comparable to the out-of-pocket costs associated with IV ketamine, some patients feel more comfortable opting for Spravato.