If you have tried two, three, or more antidepressants and still feel stuck, you are not alone, and it is not a personal failure. For many people, depression does not respond to the first treatments offered. The good news is that our understanding of depression has changed a great deal over the past 25 years, and that shift has opened new treatment options, including SPRAVATO® (esketamine) nasal spray, which we offer at our San Diego office.
This post draws on a conversation with Dr. John Krystal, Chair of Psychiatry at Yale University, whose research team helped discover ketamine's rapid antidepressant effect. My goal is to explain, in plain language, what happens in the brain and what treatment actually looks like.
Depression Is More Than Feeling Sad
Everyone has sad or discouraged days, and most people bounce back. Major depression is different. It can last for months or years and affect sleep, appetite, energy, concentration, motivation, relationships, and the ability to enjoy anything at all. It is a medical illness, not a weakness of character.
Depression also involves the whole body. Research links it to the stress-response system, inflammation, sleep and circadian rhythms, metabolism, and heart health. That is one reason untreated depression can make other medical conditions harder to manage, and why getting effective treatment matters.
Beyond the "Chemical Imbalance" Story
For decades, many people were told that depression is caused by "low serotonin." Medications like sertraline (Zoloft), escitalopram (Lexapro), and fluoxetine (Prozac) affect serotonin, so the idea made sense. But research showed that simply lowering serotonin does not reliably cause depression in healthy people. The explanation was too simple.
Scientists began to look at how brain cells communicate and adapt. Much of that communication depends on glutamate, the brain's main "go" signal. Glutamate is central to learning, memory, and the brain's ability to rewire itself, known as neuroplasticity.
A Surprising Discovery at Yale
Ketamine has been used as an anesthetic since the 1960s. In the 1990s, Yale researchers gave low doses to study glutamate, not to treat depression. They noticed something unexpected: a few hours after the medication's effects wore off, participants' depression began to lift, sometimes noticeably by the next day. Their landmark study was published in 2000.
Two things stood out:
- Speed. Standard antidepressants usually take weeks. Ketamine sometimes worked within hours to a day.
- Timing. The dreamy or "floaty" feeling during treatment faded before the mood benefit peaked. The improvement was not about feeling high. Ketamine seemed to set off a biological process that kept going after the medicine left the body.
What Happens in the Brain: Stress, Synapses, and Repair
Think of your brain as a network of roads connecting important areas for mood, motivation, and stress. Chronic stress, trauma, inflammation, and genetics can weaken or wash out some of those roads. Brain cells lose connections (called synapses), and the circuits that regulate mood become rigid and less able to adapt.
Ketamine and esketamine act on a glutamate receptor called the NMDA receptor. This triggers a cascade that includes BDNF (brain-derived neurotrophic factor), a protein that works a bit like fertilizer for brain cells. Research suggests this can:
- Strengthen existing connections that stress has weakened
- Help form new connections between brain cells
- Improve communication across mood-related brain networks
In short, the treatment may help the brain rebuild some of the roads that depression has worn down.
Ketamine vs. Esketamine (SPRAVATO®): An Important Difference
Ketamine is made of two mirror-image molecules. Esketamine is one of them, and it is the active ingredient in SPRAVATO®.
- SPRAVATO® (esketamine nasal spray) is FDA-approved for adults with treatment-resistant depression (alone or with an oral antidepressant), and for depressive symptoms in adults with major depressive disorder with acute suicidal thoughts or behavior (together with an oral antidepressant).
- IV or compounded ketamine is FDA-approved as an anesthetic. Its use for depression is off-label.
- Compounded nasal or oral ketamine is not the same as SPRAVATO®. The device, dose consistency, absorption, research, and safety oversight all differ.
Who May Be a Good Candidate?
SPRAVATO® may be worth discussing if you are an adult who:
- Has tried at least two antidepressants at adequate dose and duration without enough relief
- Still struggles with low mood, loss of interest or pleasure, fatigue, poor concentration, or withdrawal from people and activities
- Finds that depression is affecting work, school, relationships, or daily life
We will review your history, other medical conditions (including blood pressure), current medications, and substance use to decide together whether it is a safe and appropriate fit.
What a SPRAVATO® Visit Looks Like
SPRAVATO® is never taken home. It is self-administered in our office under the supervision of our clinical team, as required by the FDA's safety program (REMS).
- Check-in: We review how you are doing and check your blood pressure.
- Treatment: You use the nasal spray device yourself while we guide you.
- Observation: You relax in a comfortable space for at least two hours while we monitor you. Some people feel temporarily dissociated, sleepy, dizzy, or notice changes in perception. These effects usually fade within that window.
- Going home: You will need someone to drive you. Do not drive or operate machinery until the next day after a restful night's sleep.
Typical schedule: treatment usually starts twice a week for the first four weeks, then once a week, and then once a week or every other week for maintenance. Your schedule is personalized. If you stay well, we may space treatments further apart. If symptoms begin to return, we can adjust. Dr. Krystal describes this as a partnership between clinician and patient, and that is exactly how we approach it.
Why Supervised Treatment Matters
Ketamine-related medications can be misused and carry a risk of dependence. Using them at home whenever stress hits can shift treatment into an unhealthy pattern. Supervised, scheduled treatment keeps the focus on healing with consistent doses, safety monitoring, and ongoing psychiatric care.
Opening a Window for Change
This is one of my favorite parts to explain to patients. Esketamine does not erase memories or solve life's problems. What it may do is open a temporary window when the brain is more flexible and able to form new patterns.
What you do during that window matters. You can help your brain hold onto healthier patterns with:
- Therapy, including CBT and behavioral activation
- Consistent, restful sleep
- Regular movement and exercise
- Time with people who support you
- Stress management and meaningful daily routines
- Reducing alcohol and other substances
The medication can create an opportunity. Your daily experiences help decide how that opportunity is used.
Looking Ahead
Researchers are now exploring how the brain's immune cells, called microglia, and inflammation may play a role in depression and in how ketamine works. They are also working on treatments that may last longer with fewer side effects. This research is promising, but still early and not yet part of routine care.
The Bottom Line
Ketamine research changed how psychiatry understands depression. Rather than a simple "missing chemical," depression is increasingly seen as a problem with how brain networks connect and adapt under stress. Treatments like SPRAVATO® may help the brain begin that recovery much faster than traditional antidepressants for some people.
SPRAVATO® in San Diego at NextGen Psyche and Wellness
At NextGen Psyche and Wellness, we look at the whole person: your history, stressors, sleep, relationships, and goals, not just a diagnosis. If you are living with depression that has not improved with other treatments, we would be glad to talk with you about whether SPRAVATO® may be right for you. Care is available in English, Spanish, and Tagalog at our office at 5222 Balboa Ave., #43, San Diego, CA 92117.
Call 626-371-3053 or email info@nextgenpsycheandwellness.org to schedule a consultation.
If you are in crisis or having thoughts of harming yourself, call or text 988 (Suicide & Crisis Lifeline) or call 911. SPRAVATO® is not a substitute for emergency or hospital care.
This article is for educational purposes and is not medical advice. SPRAVATO® has important safety information, including risks of sedation, dissociation, increased blood pressure, respiratory depression, misuse, and suicidal thoughts in young adults. It is available only through a restricted program. Its effectiveness in preventing suicide or reducing suicidal thoughts or behavior has not been demonstrated. Talk with a qualified clinician about whether it is right for you. Source: Learning & Living STEMM in Connecticut podcast (CASE), "How Ketamine is Rewriting the Biology of Depression," with John H. Krystal, MD.