Esketamine (Spravato) for Treatment-Resistant Depression: Will it Live Up to Expectations?

The FDA’s recent approval of Esketamine (Spravato by Janssen Pharmaceuticals) has been met with much excitement (and some controversy) for it’s potential to help people with treatment-resistant depression. Despite it being a potentially life-threatening condition treatment-resistant depression medication options are limited. 12-20% of people diagnosed with major depression don’t respond to conventional antidepressant treatment.

According to the National Institute of Mental Health (NIMH) “depression is responsible for up to 70 percent of psychiatric hospitalizations and about 40 percent of suicides.” Here is more of what they say:

Each year, 9.5 percent of the population, or about 20.9 million American adults, will struggle with depressive illness. MDD is a recurring and chronic illness, frequently returning for two or more episodes, with episodes that often last two years or more. Depression is currently the fourth most disabling illness worldwide, and according to the World Health Organization, it will be the second leading cause of disability by the year 2020. About 10 percent of men and up to 25 percent of women will experience depression in their lifetime.

What is Treatment-resistant depression?

Treatment-resistant depression is defined as patients with Major Depressive Disorder that haven’t responded to treatment despite trying at least 2 antidepressants (at adequate doses for an adequate duration) during the current episode of depression.

How is Esketamine different from Ketamine?

You may have already heard of ketamine, an FDA-approved anesthetic that has been around for decades. On a darker side, Ketamine is known as “Special K”, an illegal hallucinogenic club drug that is infamously considered one of the more common date-rape drugs.

Ketamine is prescribed “off-label” for treatment-resistant depression at Ketamine infusion centers where a person goes to get an intravenous (IV) infusion of the medication. These centers have been gaining in popularity across the country and are available to those who can afford the treatment.

Esketamine is like a cousin to Ketamine.

Because Ketamine isn’t FDA approved for depression insurance coverage is spotty or non-existent. This means that patients desperate to feel better are spending a ton of money to get treatment. With FDA approval for Esketamine, one hope is that insurance will begin to cover this costly, but potentially life-saving treatment. Each session is estimated to cost $590-$885.

Facts about Esketamine (Spravato):

Esketamine (Spravato), a nasal spray, is a schedule III controlled substance because of its potential for abuse and misuse.
Esketamine will be highly regulated because of the concerns about abuse. It has to be given at a treatment center under supervision and cannot be taken home.
This medication works on NMDA receptors in the brain targeting glutamate. Traditional antidepressants target the serotonin, dopamine, and norepinephrine systems.
The mode of action as an antidepressant is still considered unknown.

Esketamine is used in conjunction with starting a new (for the person) oral antidepressant. It was not studied without an antidepressant.
Prior to treatment, a person is not allowed to eat for 2 hours or drink for 30 min.
Once dosed, it reaches maximum concentration within 20-40 minutes and effects can be felt within hours. This is vastly different than the effects from typical antidepressants which take weeks to months to provide benefit in those that respond.
A person receiving treatment must be monitored at the medical office for at least 2 hours before they are able to leave.
Esketamine may impair attention, judgment, reaction speed, and motor skills so after treatment person is not allowed to drive or operating machinery until the next day

The current treatment regimen for Esketamine (Spravato):

2 times per week for 4 weeks,
then 1 time per week for 4 weeks,
then 1 time every 2 weeks for 4 weeks

The optimal treatment schedule (includes deciding which dose to use 56mg vs 84mg, dosing frequency, and length of treatment/maintenance) will likely only be determined with more experience with this medication.

Studies of the effectiveness of Esketamine:

This is where some of the controversies around Esketamine’s fast-track FDA approval come in. Results are promising but mixed in terms of effectiveness. Only 1 of 3 short term trials showed statistically significant benefits and these benefits were not long lasting (“some effect at 2 days”).

The long-term trial did show that for patients that were stabilized by Esketamine, they had a longer time until the return of depressive symptoms (51%) as opposed to if they received an inactive (placebo) nasal spray.

Some people feel that the risks of abuse and lack of robust evidence didn’t warrant the approval by the FDA. However, others feel the approval was justified because treatment-resistant depression medication options are so few for an illness which can be life-threatening.

Clearly, more data is needed on short-term and long-term effectiveness and the ideal maintenance plan. Perhaps, as the optimal treatment and maintenance schedules are defined, there will be improvements in long-term efficacy data.

Potential Side Effects of Esketamine:

Dissociation (difficulty with attention, judgment, and thinking)
Sedation, decreased feeling or sensitivity, lethargy, feeling drunk
Increased blood pressure
Dizziness, vertigo
Anxiety
Nausea, vomiting

Per Janssen:

Most adverse events were mild or moderate in severity, and were typically observed on nasal spray dosing days, and generally resolved the same day.

Will Esketamine (Spravato) live up to expectations?

There is still much to learn about Esketamine (Spravato) but I am hopeful that this will be one more way to provide desperately needed relief for people suffering from treatment-resistant depression.