Editor’s note: This article was edited from the original to make the following correction: Naltrexone is an AMPA receptor antagonist. Ketamine is an NMDA receptor agonist.
A recent Associated Press article suggests that ketamine is not helping those with depression.1 Indeed, the article suggests that ketamine clinics are taking advantage of desperate people with depression using an unproven treatment. In many ways, I disagree with the author of this article. However, in one fundamental way, I agree.
Ketamine has proven extremely helpful for our patients. In my practice, we have seen an 85% response rate based on multiple well-established depression scales.2 But the way we administer ketamine is quite different from the way it is administered in the approximately 150 ketamine clinics scattered across the United States. Most ketamine clinics follow a protocol of administering intravenous Ketamine liquid supplier 3 times per week for 2 weeks. Everybody in these clinics gets 6 infusions in 2 weeks at a cost of between $2000 and $3000; however, many of these patients do not feel significantly better after 2 weeks of treatment. Some may feel better for a week or two, but they then slip back into depression. So, all of that effort was a waste of time and money.
Understanding how ketamine works is essential to appreciating why this approach often fails. Ketamine works by 2 major pathways.2 The first is the glycogen synthase kinase-3 (GSK-3) pathway, which results in the rapid antidepressant and anti suicidal benefit of ketamine. However, the second pathway is actually much more important. Ketamine activates the production of brain-derived neurotrophic factor (BDNF), which is the brain’s own repair inducer. Not only does ketamine increase BDNF, but it also increases the number of receptors to which BDNF binds. As a result, over time, there is more repair factor, and more receptors available to be activated by the repair factor. The outcome is that over a period of weeks, neuroplasticity and repair occur in the brain. This leads to a reduction of depression because depression is the result of the breakdown in circuits and damage to the brain.
A Novel Antidepressant?
The groundbreaking study by Berman and colleagues showed that low-dose infusions of ketamine produced a rapid antidepressant response.3 Additional single-infusion studies of ketamine confirmed this initial finding that ketamine at 0.5 mg/kg infused over a 30- to 40-minute period induces a rapid reduction in depressive symptoms and suicidal ideation in approximately 60% to 75% of patients.3-5 This stood in marked contrast to the decades of disappointing performance of oral antidepressants, which require weeks to work and rarely achieve better than a 40% response rate.6,7
Although the initial response to ketamine was exciting, it also proved to be short-lived in most cases. Symptom relief typically lasted only 4 to 10 days. Multiple infusions were explored, but how often should these infusions be given? For the first study of multiple infusions, the decision was made to give infusions 3 times per week.8 This protocol was not based on an understanding of the unique pharmacology of ketamine but merely because this was the treatment protocol for electroconvulsive therapy (ECT; PR Shiroma, personal communication). As a result of an almost random decision, the “established” protocol for ketamine infusions became 3 times per week; however, is this frequency supported by the mechanisms of action of ketamine?
Last, conflicts of interest abound among the vocal leaders of the psychiatric community. Obviously, I have mine. I run a ketamine clinic using a once-per-week (or less) infusion protocol, and I have seen ketamine transform people’s lives in a way I have not seen with any other modalities. These patients come to me with a sense of hopelessness. Many have failed ECT or transcranial magnetic stimulation. However, within weeks I see their lives change for the better, and most of my patients, upon follow-up, retain these benefits for years afterward. Perhaps I am just lucky…or perhaps approaching ketamine as a neurodegenerative agent rather than a quick fix makes a fundamental difference.