Ketamine for treatment-resistant depression: What you need to know

Finding relief for depression can be a frustrating experience. While taking an antidepressant or going to psychological counseling (psychotherapy) may work for most people, these standard treatments aren’t enough for others. Symptoms may not improve much or at all, or they may improve but keep coming back. These are the hallmarks of treatment-resistant depression (TRD).

Estimates vary for how common TRD is. One recent study in the Journal of Clinical Psychology estimated that almost a third of the nearly 9 million people in the United States treated for depression each year have TRD. Given how common TRD may be, limitations in medication options — typically a crucial component of depression treatment plans — are a significant roadblock. However, there is hope.

Ketamine, a drug available in intravenous (IV) and nasal spray (esketamine) forms, is being actively studied for TRD treatment. Both ketamine and esketamine are given in a doctor’s office or a clinic, and each is typically used alongside another antidepressant.

IV-infused ketamine is an FDA-approved anesthetic for surgical and medical procedures. In recent years, ketamine has increasingly been used as an antidepressant to treat TRD — considered off-label use. Ketamine delivered in low doses can provide rapid relief of TRD lasting for days to weeks. Usually, it’s given in decreasing frequency over several weeks, starting with two doses a week for 2 to 3 weeks, then once weekly, then once monthly and then hopefully tapering off. Response rates as high as 70% have been observed in clinical trials involving regular infusions.

Esketamine (Spravato) was approved by the FDA in 2019 to treat TRD. Its rapid delivery system means depression symptoms can ease within several hours. Esketamine is administered as a squirt in each nostril, followed by a two-hour monitoring period. Standard dosing involves taking the medication twice a week for about four weeks, then switching to once a week for another four weeks and then tapering off over time. Research has shown that esketamine can significantly reduce depression symptoms — relief that can last weeks after treatment ends.

Though they’re far from perfect treatments, ketamine and esketamine mark a breakthrough, as they’re the only fast-acting antidepressants available. Standard antidepressants generally take several weeks to provide relief.

Ketamine for depression: A unique weapon in the treatment arsenal

Ketamine and esketamine work differently from standard antidepressants. Selective serotonin reuptake inhibitors (SSRIs), for example, ease depression by increasing levels of serotonin, a chemical messenger carrying signals between brain cells. SSRIs block the reabsorption (reuptake) of serotonin, making it more available in the brain.

Ketamine and esketamine, on the other hand, are thought to create more connections (synapses) between brain cells, a process thought to ease depression and decrease suicidal thoughts. With depression, people usually have fewer of these connections.

In the past, there was speculation that ketamine masked depression by making a person feel “high.” This theory has since been debunked. Ketamine doesn’t remain in the system very long, yet research shows that people treated with it feel relief in the days and weeks after they stop taking it.

More research is needed to compare ketamine and esketamine directly. However, some research has suggested that the IV-infused drug provides a faster response than the nasal spray.