Esketamine and racemic ketamine
Some research shows a new drug called ketamine is effective in the treatment of depression. Ketamine is available in two forms: Esketamine and racemic ketamine. Racemic ketamine (used in ketamine infusion, aka IV ketamine) has been shown to improve both typical and atypical symptoms of depression.
It is not clear how effective racemic ketamine is compared to esketamine (marketed as a nasal spray called Spravato).
However, new research by Bahji and colleagues—from Queen’s University in Canada and the National Institute of Mental Health in the US—suggests racemic ketamine might be more effective than esketamine. Published in the January 2021 issue of Journal of Affective Disorders, the article reports the results of the “first systematic review and meta-analysis that has compared the performance of intravenous ketamine to intranasal esketamine for the treatment of unipolar and bipolar depression.”
It should be noted that esketamine (Spravato) was approved by the US Food and Drug Administration (FDA) for the treatment of depression in 2019. Ketamine infusion has been used off-label only and has yet to be approved by the FDA. Does this mean IV ketamine is necessarily inferior to Spravato? For an answer to this question, let us examine the findings of the paper by Bahji et al.
Sample and methods
The authors searched electronic databases for randomized controlled trials involving the use of intranasal esketamine or intravenous ketamine to treat depression. They included studies where the drug was used alone and studies where it was used as an augmenting agent—meaning in addition to another antidepressant medication, such as a selective serotonin reuptake inhibitor (SSRI), like Prozac or Zoloft.
The final list of trials to be included in the meta-analysis and systematic review consisted of 24 randomized controlled trials—1877 participants; 61% females; average age ranging from 36 to 70 years; 98% with major depression and 2% with bipolar depression.
In most of the investigations included in the meta-analysis, the drug had been used as an augmenting agent. In three-quarters of the trials, participants had depressive symptoms that had not responded to previous treatments. In other words, they had treatment-resistant depression. However, depending on the investigation, treatment-resistant depression was defined differently. The most common definition of treatment-resistant depression (used in over 60% of trials) was a lack of response to two or more antidepressants.
Results: Comparing esketamine and racemic ketamine
The results showed that, compared with esketamine, racemic ketamine (IV ketamine) produced a greater response (rate ratio = 3.0 vs. 1.4), remission rate (ratio rate= 3.7 vs. 1.5), and lower dropouts (rate ratio = 0.8 vs. = 1.4).
Thus, compared to “intranasal esketamine, intravenous racemic ketamine demonstrated more significant overall response and remission rates, as well as lower drop-outs due to adverse events” (p. 548).
The data showed a “clear and consistent antidepressive effect of ketamine vs esketamine treatment, relative to a variety of control conditions, beginning within hours of administration, and lasting up to 7 days after a single dose” (p. 549).
If so, why has only intranasal esketamine (Spravato) been approved by the FDA for the treatment of depression?
Perhaps IV ketamine has more serious side effects; then again, the present review showed a lower drop-out rate due to adverse events in patients treated with IV ketamine compared with Spravato.
A more likely explanation is that the lack of FDA approval is related to a lack of quality research on the long-term effects (e.g., safety, efficacy) of ketamine infusion.
IV-ketamine for the treatment of depression: Mechanisms of action
How does ketamine work? In other words, what are the mechanisms of ketamine’s antidepressant effects?
Ketamine appears to block NMDA receptors; however, this mechanism does not explain certain findings (given ketamine’s short half-life).
Specifically, the mild dissociative effects of ketamine, which occur shortly after ketamine administration, dissipate soon (probably because ketamine is metabolized quickly). Yet, the antidepressant effects of ketamine, which can be observed after two hours, are often sustained for about a week. This suggests “ketamine initiates a cascade of events that results in a rapid response,” and this response is “sustained even after the drug has been [metabolized]” (p. 29).
Some research suggests the antidepressant effect of ketamine requires the activation of AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and BDNF (brain-derived neurotrophic factor). Exactly how this occurs and whether other mechanisms are involved (e.g., opioid receptors) remain to be determined.
A better understanding of the mechanism of the antidepressant effects of ketamine is important and can help scientists develop more effective ketamine interventions for treatment-resistant depression.