Q: Why is this a “banner day” for psychiatry?
A: This is truly the first new option for depression in 60 years. The selective serotonin reuptake inhibitors (SSRIs) developed in the mid-’80s were not truly new, not much different from the monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants. In fact, they work much like watered-down MAOIs. Esketamine works by a truly novel mechanism.
Even though it constitutes a relatively new treatment, ketamine is a very old medicine, and we probably know more about the pharmacology and mechanisms in depression than for the SSRIs.
The idea of SSRIs working by increasing levels of neurotransmitters like serotonin has never held water. We never really believed that, but for people who respond to them – and many are helped – what is really happening weeks to months down the line is that these drugs increase the plasticity of the brain. Depression, like other mental health conditions, disrupts connections between important brain regions, reducing the number, function, and quality of the connections, and we believe SSRIs improve these.
Ketamine does these same things by a different route and much, much more quickly.
Q: What is esketamine’s method of action, and how long will a dose last?
A: Ketamine and esketamine bind to and block glutamate N-methyl-D-aspartate (NMDA) receptors. This leads to the release of several chemical messengers, the result of which increases the production of neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF), that play a key role in healing damaged connections in the brain. A single dose of esketamine would only be expected to relieve depression symptoms for days, up to a week or 2. Multiple doses over the first few weeks can extend the durability of response to several weeks and sometimes months.
It is not true for every patient, but some do have improvement within 2-4 hours that correlates with physiologic changes. Others can be later responders and require up to 6 exposures.
Q: The FDA approval requires those who administer the drug to complete special training and meet licensure requirements. Is this realistic for small practices?
A: Initially, not every psychiatrist will be able to offer esketamine, and I think it might be beyond the reach of small practices, and that’s probably okay. Enough people and enough centers will be able to offer it to meet the initial demand.
Q: Is esketamine “better” than ketamine infusions? With the approved drug available, will ketamine infusion clinics still have a place?
A: There are major pros with this. The FDA approval takes out of the gray area of off-label administration. It will most likely be covered by insurance now – a huge advantage that will put this in the reach of so many patients who haven’t been able to access this treatment.
I think that, because there are advantages and disadvantages for both IV ketamine and nasal esketamine, they will happily coexist for years to come. However, because nasal esketamine will likely be restricted to prescription by psychiatrists, it may have more impact on non-psychiatrist-led practices. In this way,
Dr. Steven Levine is the founder of, which operates nine clinics providing ketamine treatment for depression.