Spravato is the brand name for esketamine, the S-enantiomer of racemic ketamine. Racemic ketamine is a mixture of equal parts of the S-enantiomer (esketamine) and R-enantiomer (arketamine). Spravato and racemic ketamine have been used for various indications, including treatment-resistant depression (TRD). Here, we compare and contrast the advantages and disadvantages of Spravato versus racemic ketamine.
Advantages of Spravato (esketamine):
- Potentially greater potency: Esketamine is believed to be more potent than arketamine, with some studies suggesting it may be approximately twice as potent as racemic ketamine regarding antidepressant effects (Singh et al., 2016).
- FDA-approved: Spravato is the first and only FDA-approved ketamine-derived therapy for treatment-resistant depression (in conjunction with an oral antidepressant), which lends credibility and allows for better insurance coverage (FDA, 2019). (But see below, as FDA-Approval may mean little.)
Disadvantages of Spravato (esketamine):
- Cost: Spravato, as a patented medicine that can only be administered in-clinic, is typically more expensive than racemic ketamine, which will limit access for some patients (Cristea & Naudet, 2019).
- Limited evidence: While esketamine is effective in some studies, more research is needed to establish its long-term efficacy and safety, especially compared to racemic ketamine (Daly et al., 2019).
Advantages of racemic ketamine:
- Broader clinical experience: Racemic ketamine has been used longer and has more extensive clinical experience than esketamine alone. It has been studied for various indications, including depression, pain management, and anesthesia (Zanos et al., 2018).
- Cost-effectiveness: Racemic ketamine is generally less expensive than Spravato, making it more accessible for patients who may not have insurance coverage or the financial means to afford Spravato (Cristea & Naudet, 2019).
- Disadvantages of racemic ketamine:
- Lack of FDA approval for depression: Racemic ketamine is not FDA-approved for treating depression, which may limit insurance coverage and access to treatment for some patients.
- Potential for more side effects: Racemic ketamine contains both the S-enantiomer (esketamine) and R-enantiomer (arketamine), suggesting, theoretically, a broader range of side effects. However, research comparing the side effect profiles of racemic ketamine and esketamine is limited (Zanos et al., 2018). In fact, the S-enantiomer (esketamine) is regarded as having much more psychedelic side-effects than its sibling, the R-enantiomer (arketamine).
That Spravato is more potent than racemic ketamine or arketamine is a red-herring argument. It’s probably true that a given level of subjective dissociative experiences can be achieved on a lower dose of Spravato than racemic ketamine. So what? Are we in it for more highly dissociative experiences? Or, for the therapeutic benefit? It is doubtful that more highly dissociative experiences are more therapeutic than less dissociative experiences. Moreover, if our goal really is higher dissociative experiences then this can be achieved by increasing – doubling – the dose of racemic ketamine.
The evidence leans toward the isomer arketamine to have the more therapeutic effect. If this is true, then Spravato – lacking the arketamine isomer – should be expected to be less effective than arketamine or racemic ketamine. Moreover, it’s also possible that arketamine and esketamine have a synergetic effect that is not available from the two pure isomers.
In summary, Spravato (esketamine) offers potential advantages such as greater potency and FDA approval for treatment-resistant depression but may be more expensive and have limited long-term evidence compared to racemic ketamine. Racemic ketamine has the advantages of more comprehensive clinical experience and cost-effectiveness but lacks FDA approval for depression and may have a broader range of side effects.
We urge prospective patients not to read more into the FDA Approval of Spravato than it deserves. FDA Approval, in the case of Spravato, means next to nothing.
First, Spravato, together with an oral antidepressant, was trialed vs. placebo with an oral antidepressant. There were five clinical trials of which Spravato passed one or two, at most three, but failed two. https://en.wikipedia.org/wiki/Esketamine#Availability Two FDA panelists reviewing Spravato for approval voted against approval; 14 panelists voted to approve.
“The FDA normally requires at least two positive short-term efficacy studies for approval of antidepressants, but this requirement was loosened for esketamine and a relapse-prevention trial was allowed to fill the place of the second efficacy trial instead.[21][23] This is the first time that the FDA is known to have made such an exception and the decision has been criticized as lowering regulatory standards.”
https://en.wikipedia.org/wiki/Esketamine#cite_note-pmid31841104-23
Spravato demonstrated efficacy vs. a placebo. We applaud this development as a modest step forward in establishing the legitimacy of ketamine in general, albeit not in the racemic form.
The FDA Approval process was not a “bake-off” between either the :
- S-enantiomer (esketamine) vs. R-enantiomer (arketamine); nor,
- S-enantiomer (esketamine) vs. racemic ketamine (the S+R-enantiomers)
The FDA Approval process tells us absolutely nothing about whether the S-enantiomer (esketamine) is more effective than the R-enantiomer (arketamine) or racemic ketamine, the combination of the two enantiomers.
In fact, some studies comparing the S-enantiomer to racemic ketamine show that racemic is the more efficacious form. See, for example, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704936/
“Findings: 24 trials representing 1877 participants were pooled. Racemic ketamine relative to esketamine demonstrated greater overall response (RR = 3.01 vs. RR = 1.38) and remission rates (RR = 3.70 vs. RR = 1.47), as well as lower dropouts (RR = 0.76 vs. RR = 1.37).”
“Conclusions: Intravenous ketamine appears to be more efficacious than intranasal esketamine for the treatment of depression.”
See this recent study, which evidences across 3299 patients that Spravato is less effective than racemic ketamine.
Moreover, the S-enantiomer has greater side-effects:
“. . . esketamine generally has a more dissociative or hallucinogenic effect while arketamine is reportedly more relaxing.”
Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (February 1997). “Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)”. European Neuropsychopharmacology. 7 (1): 25–38. doi:10.1016/s0924-977x(96)00042-9. PMID 9088882. S2CID 26861697.
Spravato comes in two strengths: 56 mg, or 84 mg. A patient is typically administered the 56 mg dose and may be administered the 84 mg dose if he doesn’t respond adequately to 56 mg. There are no intermediate doses. A practitioner may not administer a dose between 56 and 84 mg. Nor may the practitioner deliver a higher or lower dose then these two mandated doses.
There is evidence that each patient has a dose-response curve shaped like an inverted U. At a dose – particular to each patient – the best response is observed. At either a higher or lower dose, a less efficacious response will be achieved. If this is true, then Spravato’s doses of 56 or 84 mg are just perfect for a patient whose personal dose-response curve peaks near either – let’s say – 55 or 85 mg.
But what should we surmise if a particular patient’s personal dose-response curve peaks at – let’s say – 70 mg (basis intra-nasal)? This unlucky patient will probably experience a sub-optimal response at either of Spravato’s only two doses: 56 or 84 mg. And there is nothing that his provider can do to titrate Spravato to this patient’s optimal response.
This example – a patient whose personal dose-response curve peaks at precisely 70 mg is contrived to make a rhetorical point. Likely, few patients’ dose-response curves peak between 69 – 71 mg. The point to understand here is to consider the choice between:
- protocol-driven medicine; vs.,
- patient–response-driven medicine.
The Authoritarian-Regulatory-Medical-Establishment mind-frame is about dictating what prescribers may or may not do in treating patients. As-if patients are to fit fixed protocols vs. protocols designed to discover optimal patient responses.
Spravato is approved exclusively for:
- TRD – Treatment Resistant Depression; or,
- SI – Suicidal Ideation
Evaluation criteria are strict. See: https://www.evicore.com/-/media/files/evicore/clinical-guidelines/spravato-esketamine-nasal-sprayv102023eff06012023pub03222023.pdf.
If your diagnostic criteria don’t clearly fit within one or the other of these two approved conditions, you will not be given Spravato.
If you have medical insurance covering Spravato, meet the diagnostic criteria, and live close to a clinic providing this form of ketamine, by all means, give Spravato a trial. If your situation does not conform to all three of these conditions, you are probably better off with a trial of racemic ketamine.
Bear in mind that the popular press slovenly sucks up to the Official narrative published by the Autoritarian-Government-Medical-Establishment. This includes quotes and video snippets from clinicians and researchers who are members of this establishment. Yes, they desperately need to appear to be authoritative. They need to quote FDA-Approved and “randomized placebo-controlled double-blind gold-standard research.” They don’t add “financed and conducted by BIG-Pharma manufacturers promoting a patent medicine.” They don’t cite articles that report the findings of a bake-off of Spravato against racemic ketamine or arketamine alone.
We are not here to condemn Spravato. We applaud J&J for investing in a form of ketamine. Whether better, worse, or competitive with arketamine and racemic ketamine, they contributed to the science of ketamine for mental health. We should all be grateful for their investment. But we should also be cognizant of the objective science. And the mainstream media that you read is pandering to the Autoritarian-Government-Medical-Establishment. As long as you bear that fact clearly in mind, you will know what you are shopping for.
Cristea, I. A., & Naudet, F. (2019). Ketamine for depression: a drug fast-tracked, but for whom? Epidemiology and Psychiatric Sciences, 28(5), 497-500.
Daly, E. J., Singh, J. B., Fedgchin, M., Cooper, K., Lim, P.,Shelton, R. C., … & Wajs, E. (2019). Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA psychiatry, 76(2), 155-165.
FDA. (2019). FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. Retrieved from https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified
Singh, J. B., Fedgchin, M., Daly, E. J., De Boer, P., Cooper, K., Lim, P., … & Van Nueten, L. (2016). A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. American Journal of Psychiatry, 173(8), 816-826.
Zanos, P., Moaddel, R., Morris, P. J., Riggs, L. M., Highland, J. N., Georgiou, P., … & Zarate Jr, C. A. (2018). Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacological Reviews, 70(3), 621-660.