The Effects of Intranasal Ketamine on Treatment-Resistant Depression

As I have previously reported, off-label use of ketamine for treatment-resistant depression has resulted in numerous anecdotal reports regarding its unique mechanism of action and overwhelming success in symptom reduction among treatment-resistant and suicidal patients.

This is an important finding because approximately one-third of patients with major depressive disorder (MDD) do not respond to currently available antidepressants. As a result, The American Psychiatric Association (APA, 2016) had issued guidelines for psychiatrists who wish to use ketamine for this purpose. At the time, a slow intravenous infusion was the primary delivery system used to attain the reported results. There are of course numerous challenges and costs associated with this delivery system, including the use of a clinical facility with available advanced life support systems in place.

What Is Ketamine?

Ketamine was developed and FDA approved more than 50 years ago as a fast-acting anesthetic with an impressive safety profile. It is still used today in anesthesiology on both pediatric and adult patients and animals. Ketamine in higher doses also has unique dissociative properties, which explains its popularity as a club drug known as “Special K” in the U.S. It is currently a highly abused club drug in southern Asia today.

Intranasal Ketamine Clinical Trial

In this well-designed original research conducted by Daly and colleagues, a phase 2, double-blind, doubly randomized, placebo-controlled study was employed to assess the efficacy, safety and dose-response of intranasal esketamine hydrochloride (ketamine) in patients with treatment-resistant depression (TRD). The primary positive endpoint was a statistically significant change from baseline to day eight during each study period, measured by the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS).

This study consisted of four phases:

  1. Screening
  2. Double-blind treatment (days 1-15), composed of two 1-week periods
  3. Optional open-label treatment (days 15-74)
  4. Post-treatment follow-up at 8 weeks

The results are impressive. Change in MADRS total score in all three esketamine groups was superior to placebo (esketamine 28 mg: −4.2 (2.09), P = .02; 56 mg: −6.3 (2.07), P = .001; 84 mg: −9.0 (2.13), P < .001), with a significant ascending dose-response relationship (P < .001). Even more impressive is the continuous reduction of depressive symptoms despite reduced dosing frequency during the open-label phase.

Why Does This Matter?

First, the mortality rate for untreated and undertreated depression is between 15 and 20%. Moreover, depression and suicidality are increasing in the U.S., most notably among children and adolescents. Ketamine is thought to inhibit the N-Methyl-D-Aspartame (NMDA) system, which is unrelated to our 50-year-old catecholamine hypothesis, suggesting that the inhibition of NDMA is a viable, and perhaps primary, target for future intervention. In addition, there is growing anecdotal data suggesting that ketamine may also be a viable treatment for pain and perhaps even addictive disease.

Second, the results of this important study show that esketamine has a significant effect on symptom reduction among patients with TRD (Montgomery- Asberg Depression Rating Scale) after only one week of twice-weekly administration, which is substantially faster than the SSRIs or SSNRIs. It is also of interest that esketamine is well tolerated with few adverse effects, evidenced by the fact that a mere 5% of participants discontinued treatment during the double-blind phase. In addition, the use of an intranasal delivery system allows lower dosage compared to oral administration by avoiding first-pass hepatic metabolism.

Third, because of its low molecular weight (238 Daltons), esketamine is a good candidate for intranasal delivery because lower molecular weight improves nasal mucosa absorption. This route will get the dose to the brain rapidly, and for reasons that remain unclear, the therapeutic effect remains when using a twice-per-week dosing system.

All this is to say that compared to currently available oral antidepressant medications, which have a poor adherence rate, esketamine should vastly improve treatment adherence. Combined with few reported adverse effects, more people will get well. This is good day to be a neuroscientist.

Ella J. Daly, MD; Jaskaran B. Singh, MD; Maggie Fedgchin, PharmD; Kimberly Cooper, MS; Pilar Lim, PhD; Richard C. Shelton, MD; Michael E. Thase, MD; Andrew Winokur, MD, PhD; Luc Van Nueten, MD; Husseini Manji, MD, FRCPC; Wayne C. Drevets, MD Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression. A Randomized Clinical Trial. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.3739. Published online December 27, 2017.