N-methyl-D-aspartate (NMDA) receptor antagonists have demonstrated potential in the treatment of depression with rapid and positive results in patients who are acutely suicidal or facing treatment-resistant depression.

Treatments like intranasal esketamine, and AV-101 (an oral treatment) are in development showing a promising trajectory as treatments. In the midst of what was believed to be a breakthrough, a Stanford study recently concluded that ketamine works on the opioid system in the brain making its role as a treatment potentially more complex than previously believed.

Ketamine has been used to treat patients with major depressive disorder, pain, and suicidal ideations. It has most commonly been delivered through intravenous (IV) administration.

Ketamine, and NDMA receptor antagonists, are considered to be ‘next generation’ therapies. The reason they are referred to as such is due to the different delivery and structure of the drugs in comparison to typical therapies like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

Typical first-line treatments like SSRIs and SNRIs can take, on average, four to six weeks to work. Whereas, ketamine and its counterparts have been shown to only take hours to have an effect.

NMDA receptors, one of the glutamate receptors in the brain, are considered to contribute to pathophysiology of depressive disorders. NMDA receptor antagonists are believed to work on the receptors that cause depression to reverse or lessen symptoms.

While it rapidly treats patients, ketamine has psychotomimetic effects (experiences that can mimic symptoms of psychosis), and can only be administered through an IV. The demonstration of ketamine having strong efficacy has pushed treatments that have ketamine-like mechanisms in the brain towards development.

Intranasal esketamine ​

Carla Canuso, a psychiatrist and researcher at Janssen, is leading a clinical trial on the effect of esketamine in participants at an imminent risk of suicide. She told us esketamine is an antimere of ketamine – a branch of the molecule. Ketamine has both S and R components​, but the esketamine portion (S-Ketamine) of the molecule has a greater affinity for the NMDA receptor. As a result, esketamine can be administered in lower volumes, making it an appropriate choice for intranasal administration.

Intranasal drug delivery (INDD) allows for quick delivery of a drug to the brain without passing through the ‘first pass metabolism​’, according to Canuso. During the first pass metabolism, the drug is processed through the liver and a small portion of the dose is lost in the process making the efficacy lower or the dosage needed greater.

The nasal membrane is vascular though, and the drug can pass through the mucous membrane of the nose into the bloodstream quickly and onto the brain rapidly. Additionally, the tolerability of intranasal administration is much more convenient than IV administration.

“We like the idea of intranasal [delivery of esketamine] because we can get a pharmacokinetic profile that’s similar to that of an IV, but uses a method that’s more acceptable to patients,”​ Canuso said.

Reaching a pharmacokinetic profile of ketamine through a more convenient approach is clinically imperative to explore especially for the use in acute situations according to Canuso.

“We can engage in psychotherapies which are ultimately effective, but the treatments [for the imminently suicidal] beyond [that are] just safety measures [that] have little immediate benefit. This treatment [INDD esketamine] was of great interest to us but also to the clinical community – to have something that could work so quickly. And when I say quickly, we’re talking about hours instead of weeks,”​ said Canuso.

Due to the nature of the molecules and their effect on the brain, both ketamine and esketamine cause some degree of dissociation, said Carla. She stated the side effects to be, “a sort of sensation of floating or being disconnected from one’s self or their body.”​ However, she further explained that this side effect is predicted and often mild.

Janssen is conducting two studies: a Phase III trial of esketamine in treatment-resistant depression​, and a Phase II trial of esketamine in participants with an imminent risk of suicide,​ which follows Canuso’s proof-of-concept study after it demonstrated success.

In the trials, each patient received a dose of either esketamine or placebo, as well as an anti-depressant. “What’s made the studies successful in its enrollment is that the research really sits right on top of what is standard care,”​ said Canuso.

Suicidal patients have not often been included in clinical trials but, in this trial, patients have shown rapid success after being administered INDD esketamine, with significant changes in Montogomery-Asberg Depression Scale (MADRs) scores, which rate the severity of depression.

The treatment of severe mental illness through atypical therapies has not yet had a breakthrough. With clinical trials still obtaining data, there may be a wait until such treatments could reach patients. However, while there have been no breakthroughs, cracks are beginning to form for ‘next generation’ treatments to break down barriers.

The next article in this two-part series will look at treatments analogous to ketamine that mimic the same mode of action – without being chemically identical. In addition, the second part will look at how the controversies of this form of treatment extend beyond it simply being an illegal substance​​ and into its disputed mode of action.​​