A few years ago, the FDA approved esketamine for use against treatment-resistant depression. For lay-people like myself, this news may have raised many questions. What is esketamine? Is it different from ketamine? What is treatment-resistant depression and why is this drug special in treating it? When new drugs are introduced into the market, they are often marketed in ways that express enthusiasm for their potential. In the case for this drug, there is some concern about its specific usage that is important to note. Answering all of these questions helps us find the niche where this drug can be useful.
Ketamine is a fast acting party drug known for being an anesthetic, with esketamine being one of its two chemical forms. It is exactly its short onset of activity that makes it a prime candidate for treatment resistant depression. About 30% of patients do not respond to antidepressant treatments (Mogaddham, 2021, p. 148). And these antidepressant treatments often take weeks to take their effect (Mogaddham, 2021, p. 129). Ketamine acts through a different mechanism than antidepressants, which is not entirely clear, that allows it to not only anesthetize a patient, but also treat pain quickly (Mogaddham, 2021, pg. 11). Its effect on depression is such that it can improve symptoms within hours.
This may sound amazing, but there are many caveats associated with ketamine use that challenge the idea that it may be a miracle drug for this niche. First of course are the side effects of ketamine, including ulcerative cystitis: severe damage to the renal system (Mogaddham, 2021, pg. 23). This specific effect has been commonly observed in chronic ketamine users, presenting a significant concern for long-term use of the drug as a treatment for depression. Also challenging effectiveness of ketamine as a long term treatment is the weakness in evidence regarding its positive effect on suicidality. Only a limited number of studies have found ketamine to have positive effects on suicidal-ideation and even amongst those that have found this effect, it is limited to a short term period – suicidality then increases about a week after the treatment (Mogaddham, 2021, p 136-138). This concern brings up further questions on how the treatment is administered.
While ketamine seems to have a fast-acting effect compared to antidepressants, these ketamine treatments have to be administered multiple times a week in order to be effective (Mogaddham, 2021, p. 129-130). These frequent doses are required to prevent relapse. So while antidepressants may take effect after a certain number of days or weeks, they do provide a much more sustainable treatment schedule compared to ketamine.
Esketamine, being the specific version of the drug patented for treatment, also brings further complications into its usage. There are some theories on why esketamine was chosen over its other half, arketamine, but none of them seem to be about its effectiveness as a treatment. In fact, arketamine seems to be both more effective as a treatment for depression while also being a safer option in general with less capability to cause hallucinations (Mogaddham, 2021, p. 97-99). On top of this, arketamine also seems to be able to treat symptoms like psychosis (Hashimoto, 2023). This is important to note because prolonged ketamine usage comes at the risk of increasing sensitization to hallucinogenic states, combined with tolerance for its analgesic effects, meaning that over time, ketamine would become weaker in bringing out a desired effect while becoming stronger at eliciting an effect that is not wanted (Mogaddham, 2021, p. 134).
Considering all of this information, ketamine is definitely not a miracle drug, but it may be an effective short term treatment for individuals that did not see improvement using antidepressant medication. It carries many risks for use in the long term, so it would most likely be confined to this shorter term. The use of other forms of ketamine, namely arketamine, can also reduce some of the risks associated with the treatment. There is also some evidence that ketamine treatments can be even more effective when conjoined with psychotherapy, since the effects of the drug can facilitate the therapy process (Dore et al., 2019). This of course carries many safety concerns, but presents another avenue for the drug’s usefulness moving forward.
Dore, J., Turnipseed, B., Dwyer, S., et al. (2019). Ketamine assisted psychotherapy (KAP): Patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. Journal of Psychoactive Drugs, 51(2), 189–198. https://doi.org/10.1080/02791072.2019.1587556
Hashimoto, K. (2023). Arketamine for cognitive impairment in psychiatric disorders. European Archives of Psychiatry and Clinical Neuroscience. https://doi.org/10.1007/s00406-023-01570-5
Moghaddam, B. (2021). Ketamine. The MIT Press.
2 thoughts on “Finding a Niche for Ketamine in Treating Depression”
Hello Furqan! I enjoyed reading this article about ketamine and esketamine. What I noticed about your writing is that you take a “humble” approach, identifying as a “lay” person who might not be an expert in the respective topic. This helped me in understanding your text better because I found myself asking the same questions. This article does make me wonder how a drug can “induce” suicidal thoughts.
The book Ketamine by Bita Moghaddam is a great book. I would like to have seen more primary, empirical research articles incorporated into this blog post.