There has been a lot of buzz surrounding esketamine (brand name Spravato), a newly approved nasal spray for the treatment of depression. Many have touted it as a breakthrough in mental health treatment, claiming that it is more effective and faster -acting than traditional antidepressants. However, upon closer examination, it becomes clear that the evidence supporting esketamine's effectiveness is lacking and there may be a financial incentive for its FDA approval.
Firstly, let's address the claim of esketamine being more effective than intravenous ketamine. While it is true that both forms of ketamine have shown promise in treating depression, the majority of scientific studies have focused on intravenous infusion rather than nasal spray. In fact, a recent meta-analysis found that intravenous ketamine infusions had a significantly greater effect on depressive symptoms compared to nasal spray. This is likely due to differences in bioavailability and metabolism between the two forms of ketamine, making it important for research and treatment options to focus on the more effective method.[1]
The recent FDA approval of esketamine, a derivative of ketamine, for the treatment of depression has sparked both excitement and controversy within the medical community. While there is no denying that ketamine has shown promise in treating difficult-to-treat depression, the evidence supporting the use of esketamine may not be as robust as it seems.
Esketamine gained FDA approval based on two short-term clinical trials, both of which showed a significant improvement in depressive symptoms compared to placebo. However, these studies only followed participants for four weeks and did not include a long-term follow-up. While this may be sufficient for initial FDA approval, it is important to recognize the limitations of such short-term studies.
In the first study, 223 adults with resistant depression were randomly allocated to esketamine or placebo treatment, doubling the dose every two weeks. Significant improvements were reported in the esketamine group, although the dropout rate was notably higher compared to the placebo group, introducing potential bias and questioning the study's validity[2].
The second study employed a similar methodology, with 197 participants undergoing the same dosage escalation process. Again, results demonstrated a statistically significant improvement in depressive symptoms for those receiving esketamine[3].
Despite the encouraging results, both studies were limited by their short-term design - merely four weeks, a period insufficient to ascertain the duration of esketamine's therapeutic effect or to adequately monitor potential long-term side effects.
Moreover, the studies' design did not allow for a comparison with racemic ketamine, a cheaper and more readily available variant, which prior studies have shown to be effective in treating depression[4]. This absence of comparative data further casts doubt on the strength of the evidence supporting esketamine's FDA approval.
It is also worth noting that while esketamine has received FDA approval, it is only approved for use in conjunction with an oral antidepressant. This means that the evidence supporting esketamine's efficacy may be confounded by the effects of the concurrent antidepressant medication. In contrast, studies on intravenous ketamine have typically used a washout period to minimize any potential effects from other medications.
On the other hand, there is a substantial body of evidence supporting the efficacy of intravenous ketamine for depression. Meta-analyses and systematic reviews have consistently shown significant improvements in depressive symptoms following treatment with intravenous ketamine, with effects lasting up to several weeks. Additionally, there is some evidence suggesting that repeated doses of ketamine may lead to longer-term benefits.
Two of the most notable studies on the efficacy of intravenous ketamine for depression are by Singh et al. and Murrough et al. In a randomized controlled trial conducted by Singh et al., 72 patients with treatment-resistant depression were given either a single dose of intravenous ketamine or midazolam (a placebo). The study found that those who received ketamine had a significantly greater reduction in depressive symptoms at 24 hours and two weeks post-treatment compared to those who received midazolam [4].
Similarly, Murrough et al. conducted a randomized controlled trial on 73 patients with severe treatment-resistant depression, comparing intravenous ketamine to placebo saline infusion. They found that the ketamine group had significantly lower depressive symptoms at 24 hours and seven days post-treatment, with some patients experiencing remission [5].
These studies demonstrate the potential of ketamine to rapidly improve depressive symptoms in treatment-resistant patients. Further research is needed to explore long-term effects and optimal dosing strategies, but these findings suggest that intravenous ketamine may be a promising option for those who have not responded to traditional antidepressant medications.
Moreover, the use of ketamine for depression has opened up new avenues for understanding and treating other mental health disorders. Recent studies have shown potential efficacy in using ketamine for conditions such as post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and bipolar disorder [6][7]. This has led to the exploration of different formulations and routes of administration, such as oral or intranasal ketamine, in order to make it more accessible and convenient for patients.
So why then has esketamine received FDA approval and garnered so much attention? One possible explanation is that Janssen, the pharmaceutical company behind Spravato, has a financial incentive to push for its approval and convince insurance companies to cover the treatment. As an intranasal medication, esketamine can be easily administered in a doctor's office, making it a more profitable option than intravenous infusions that require medical supervision and specialized equipment. This raises concerns about the prioritization of profits over patient well-being and calls into question the motivations behind esketamine's FDA approval.
The financial aspects surrounding this issue demand a deeper examination. Intriguingly, ketamine, the parent drug of esketamine, is significantly less expensive. The crux of the cost for intravenous ketamine treatment is not the drug itself but rather the additional expenses incurred for the necessary medical supervision and overhead - a required presence of medical staff during administration, their salaries, and the cost of specialized equipment.
This poses a thought-provoking question - why would insurance companies willingly opt to cover the more expensive and less researched alternative, esketamine? The rationale for such a choice seems counterintuitive from a purely economical perspective. The insurers are effectively choosing to sustain higher costs for a less researched and potentially less effective treatment option. This absurdity begs us to consider that perhaps the influence of Janssen, the pharmaceutical powerhouse behind Spravato, might be subtly at play here, swaying decisions in favor of their patented product and against the broader interest of patient well-being and cost-effectiveness. The healthcare landscape should ideally be devoid of such corporate manipulations, and the welfare of the patient must always be the primary concern.
In addition to its potential as a medication, ketamine also offers insights into the neurobiology of depression. It has been found to act on certain neurotransmitter systems, particularly glutamate, which is involved in learning, cognition, and emotion regulation [8]. This has led researchers to investigate the role of glutamate dysregulation in depression and how it can be targeted for treatment.
Furthermore, the rapid onset of ketamine's antidepressant effects challenges traditional theories about the timeline of medication efficacy. It suggests that there may be alternative pathways to alleviating depressive symptoms besides the usual weeks or months it takes for traditional antidepressants to take effect. This has sparked further research into other fast-acting treatments for depression, such as psilocybin, a compound found in certain types of mushrooms that has shown promise in clinical trials [9].
Overall, the use of ketamine in treating depression marks a significant shift in our understanding and approach to mental health disorders. It not only offers a potential new treatment option for those who have been resistant to traditional methods, but it also sheds light on the complex and varied mechanisms involved in depression. As we continue to delve deeper into the neurobiology of depression, we may uncover even more effective and targeted treatments that can truly transform the lives of those suffering from this debilitating condition.
As society continues to grapple with mental health issues and search for effective treatments, it is important to critically evaluate all options and consider the motivations behind their promotion. Ketamine, in both its forms, may offer hope for those suffering from treatment-resistant depression, but it is crucial to analyze and address any potential risks and conflicts of interest in its use. Let us utilize ketamine's potential with caution and always prioritize the well-being of patients above profit. Moreover, as we continue to study the effects of ketamine on the brain and its potential as a treatment for depression, it is essential to not lose sight of the bigger picture. Mental health issues cannot be solved solely by medication; they require a comprehensive approach that includes therapy, support systems, and addressing societal factors such as stigma and access to resources.
Bahji, A., Vazquez, G. H., & Zarate Jr., C. A. (2020). Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. Journal of Psychiatric Research, 130, 76-82.
Daly EJ, Trivedi MH, Janik A et al. (2018). Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 75(4): 350-358.
Fu DJ, Ionescu DF, Li X et al. (2020). Efficacy and Safety of Esketamine Nasal Spray Plus Oral Antidepressant Treatment in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 77(5): 427-435.
Zarate CA, Singh JB, Carlson PJ et al. (2006). A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression. Arch Gen Psychiatry. 63(8): 856-864.
Murrough, J.W., Perez, A.M., Pillemer, S., Stern, J., Parides, M.K., aan het Rot, M. … Charney, D.S. (2013). Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biological Psychiatry, 74(4), 250-256.
Feder, A., Parides, M.K., Murrough, J.W., Perez, A.M., Morgan Jr., J.E., Saxena, S. … Charney, D.S. (2014). Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: A randomized clinical trial. JAMA Psychiatry, 71(6), 681-688.
Rodriguez, C.I., Kegeles, L.S., Flood, P., Simpson, H.B. (2013). Rapid resolution of obsessions after an infusion of intravenous ketamine in a patient with treatment-resistant obsessive-compulsive disorder. Journal of Clinical Psychiatry, 74(11), 1064-1066.
Abdallah, C. G., & Sanacora, G. (2018). Ketamine: a promising novel therapy for anxiety and PTSD. Trends in neurosciences, 41(9), 570-573.
Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M., Erritzoe, D., Kaelen, M., ... & Taylor, D. (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry, 3(7), 619-627