Esketamine Enhances Efficacy of Oral Antidepressants in Treating Fluctuating Depression Symptoms

If you live with depression, you probably already know it doesn’t always behave like a steady, straight line.
Some days the clouds part, other days they slam back in without warning. For many people, oral antidepressants
help a lotbut the benefits can wax and wane. This pattern, often called a fluctuating antidepressant response,
can be frustrating, exhausting, and incredibly discouraging.

Over the past few years, one treatment has attracted serious attention for exactly this problem:
esketamine nasal spray, often used together with an oral antidepressant. Originally approved for
treatment-resistant depression, esketamine acts on a different brain system than traditional antidepressants and
may help stabilize symptoms when people respond inconsistently to their usual meds.

In this guide, we’ll unpack how esketamine works with oral antidepressants, what the research actually shows
about fluctuating depression symptoms, safety and monitoring requirements, and what real-world experiences
often look likeall so you can have more informed, grounded conversations with mental health professionals.

From “Up-and-Down” Days to Fluctuating Depression Symptoms

First, a quick reality check: everyone has mood shifts. Bad traffic and no coffee will do that to anyone.
But fluctuating depression symptoms are different. Here, a person is already diagnosed with major
depressive disorder and is taking an antidepressant. They might initially feel betterless hopeless, more
energy, better sleepbut over weeks or months, the benefits come and go. Some days look almost “normal,”
others feel like a full relapse.

This isn’t simply “being moody.” It’s often a sign that:

• The current dose of the antidepressant isn’t quite enough.
• The medication helps only certain symptoms (for example, sleep improves but low mood doesn’t).
• Biological factors (like inflammation, hormonal changes, or stress hormones) are getting in the way.
• The depression is edging toward what clinicians call treatment-resistant depression (TRD)usually defined as an inadequate response to at least two different antidepressants at adequate doses and duration.

Fluctuating response is important because it increases the risk of relapse, missed work, and a general sense of
“I’ll never get better.” That’s one reason researchers began asking: could a different kind of medicine,
targeting a new pathway, help smooth out those ups and downs when used together with traditional antidepressants?

What Exactly Is Esketamine?

Esketamine is a close chemical cousin of ketamine, a medication that has been used for decades in anesthesia.
Unlike classic antidepressants that primarily work on serotonin, norepinephrine, or dopamine, esketamine targets
the glutamate system, specifically the NMDA receptor. This difference is a big part of why it acts
more rapidly than most standard antidepressants.

In the United States, esketamine is available as a nasal spray under the brand name
Spravato. It is:

• FDA-approved for adults with treatment-resistant depression and for certain adults with major depression and acute suicidal thoughts, originally as an adjunct to an oral antidepressant.
• Administered in a certified clinic under a Risk Evaluation and Mitigation Strategy (REMS) program due to safety concerns such as sedation, dissociation, increased blood pressure, and potential misuse.
• Used in carefully monitored treatment sessions, where people are observed for at least two hours after dosing and cannot drive until the next day after a full night’s sleep.

In early clinical trials, esketamine showed relatively rapid reductions in depressive symptoms compared with placebo
nasal spray when both were combined with a standard oral antidepressant. These findings helped establish its role
as an add-on option for people who weren’t getting enough relief from pills alone.

How Esketamine Works Alongside Oral Antidepressants

Think of oral antidepressants and esketamine as working two different “circuits” in the brain.
Traditional antidepressants (SSRIs, SNRIs, and others) tune the levels of monoamine neurotransmitters.
Esketamine, by contrast, appears to:

• Block NMDA receptors on certain neurons,
• Trigger a burst of glutamate release,
• Activate AMPA receptors, and
• Promote synaptic plasticityessentially helping brain cells talk to each other more efficiently.

This cascade is thought to support the repair or strengthening of neural circuits involved in mood regulation,
motivation, and emotional processing. When combined with an oral antidepressant, esketamine may:

• Provide faster symptom relief than pills alone.
• Boost response in people who only partly improved on oral medication.
• Help maintain remission when depression has been stubborn or recurrent.

Rapid Symptom Relief: What the Trials Show

Several randomized controlled trials in adults with treatment-resistant depression have shown that intranasal
esketamine added to a newly started oral antidepressant can reduce depression scores more than placebo plus
antidepressant over a period of a few weeks. In these studies, people often began to notice meaningful changes
in mood, hopelessness, or energy within days to weeks rather than the typical four to six weeks often quoted
for standard antidepressants.

Meta-analyses pooling multiple trials suggest that esketamine plus an antidepressant is associated with:

• Greater average reductions on standardized depression scales.
• Higher response and remission rates compared with antidepressant alone.
• Particularly noticeable benefits in people who had already failed several antidepressants in the past.

The effect sizes are generally described as modest but clinically meaningful. In other words, this isn’t a
magic “switch” that cures depression overnight, but for some people, it can be the difference between dragging
through each day and feeling functional enough to work, connect with others, and engage in therapy.

Staying Better: Maintenance and Relapse Prevention

Depression isn’t a sprint; it’s more like a marathon with hills, potholes, and the occasional random thunderstorm.
Long-term studies of esketamine combined with oral antidepressants suggest that continuing treatmentat a reduced
frequency after the initial phasecan help maintain gains and lower the risk of relapse in people who did respond.

Typically, treatment is more frequent at the start (such as twice weekly), then gradually tapers to weekly or
every other week, always under medical supervision. If symptoms begin to fluctuate again, clinicians may adjust
the frequency of sessions, the oral medication, or both.

Esketamine and Fluctuating Antidepressant Response (FAD)

More recently, researchers have zoomed in on people who don’t fit neatly into the “works” vs. “doesn’t work”
antidepressant boxes. Instead, they experience a fluctuating antidepressant responsesymptoms improve,
then worsen, then improve again, despite continuing the same oral medication.

In a study highlighted by pharmacy and psychiatric news outlets, a single subanesthetic dose of esketamine
was investigated as an add-on for people with major depressive disorder who had this kind of fluctuating response.
The results suggested that adding esketamine could:

• Enhance the overall antidepressant effect of the existing oral medication.
• Reduce the variability of symptom severity over time.
• Do so with a safety profile consistent with what has been seen in treatment-resistant depression trials.

These findings are still relatively early and need replication, but they support the idea that esketamine
may help “stabilize the signal” when an antidepressant is working some of the time but not reliably.

Who Might Be Considered for Esketamine Plus an Antidepressant?

Decisions about esketamine are always individualized and made between a person and their mental health team.
In general, candidates for esketamine plus an oral antidepressant often share some common features:

• They are adults with a diagnosis of major depressive disorder.
• They’ve tried at least two oral antidepressants at therapeutic doses and for adequate durations without sustained, satisfactory improvement.
• They may have partial or fluctuating responsebetter than before, but still significantly symptomatic.
• They don’t have certain contraindications (such as uncontrolled high blood pressure or specific cardiovascular or psychotic conditions) that would make esketamine too risky.
• They can attend clinic visits regularly and have transportation and support, given driving restrictions after treatment.

Esketamine is not intended as a first-line treatment for mild depression, and it is not an at-home “quick fix.”
It’s one toolsometimes a powerful onewithin a broader treatment plan that may also include oral medications,
psychotherapy, sleep and lifestyle changes, and social support.

Safety, Side Effects, and Monitoring Requirements

Here’s the part where the fine print gets real. Esketamine carries several important safety considerations,
which is why it lives inside a REMS program and must be administered in a controlled setting.

Commonly reported effects during and shortly after dosing can include:

• Dissociation (feeling detached from your body or surroundings, “dreamlike” sensations).
• Dizziness and changes in perception (for example, altered sense of time or space).
• Increased blood pressure, usually peaking shortly after dosing and then coming down.
• Nausea, fatigue, or headache.
• Sedation or feeling “out of it”, which is why people must be monitored and cannot drive afterward.

More serious but less common risks include profound sedation, respiratory depression, and rare cases of loss of
consciousness. There is also a boxed warning (similar to many antidepressants) regarding suicidal thoughts
and behaviors, particularly in younger adults, and a warning about the potential for abuse and misuse.

Because of these risks, clinics typically:

• Screen people carefully before starting treatment (including psychiatric and medical history, substance use history, and current medications).
• Monitor vital signs, level of consciousness, and mental status for at least two hours after each dose.
• Provide clear instructions about activity restrictions (no driving, operating machinery, or signing important documents until the next day).
• Reassess regularly to ensure that the benefits justify continuing treatment.

If you’ve ever wondered why esketamine isn’t offered in a “drive-through” format, this is why.
The structure is designed to keep people as safe as possible while still making the treatment accessible.

Practical Questions People Often Ask

How fast does it work?

In many clinical studies, some people reported noticeable improvement within 24 hours of the first or second dose,
especially in terms of intense hopelessness or suicidal thinking. Others needed multiple weeks of treatment before
gains became clear. Everyone’s timeline is a little different, and response is never guaranteed.

Do oral antidepressants still matter if I’m on esketamine?

Yes. Even though esketamine can act relatively quickly, oral antidepressants contribute to the overall
stabilization of mood over time. In the original approval studies, esketamine was almost always used as
an add-on to a standard antidepressant, not as a replacement. More recent approvals allow for monotherapy
in certain situations, but many people still receive it in combination with pills, especially when addressing
fluctuating responses.

Does esketamine “fix” fluctuating symptoms forever?

Unfortunately, no treatment comes with a lifetime “no relapse” guarantee. Some people experience long periods
of stability with maintenance sessions spaced out over weeks. Others may still have occasional dips that need
additional support, dose adjustments, or complementary strategies like psychotherapy, sleep optimization,
or stress management.

Limitations of the Current Evidence

As exciting as the data can look, it’s important to keep expectations grounded:

• The benefits of esketamine are often described as modest on averagethough individual responses can be stronger.
• Most trials look at specific patient groups with well-defined inclusion and exclusion criteria. Real-world patients can be more complex.
• Long-term, real-world safety and effectiveness data are still accumulating.
• Cost, insurance coverage, and logistical barriers (time off work, transportation, proximity to a REMS-certified clinic) are genuine challenges.

That said, for adults living with stubborn, fluctuating depression symptoms despite multiple medications,
esketamine plus an oral antidepressant represents a meaningful addition to the toolkitespecially when used as
part of a comprehensive, personalized treatment plan.

Real-World Experiences With Esketamine and Oral Antidepressants

Clinical trials give us numbers, graphs, and p-values. Real life, however, shows up as alarm clocks, late-night
worries, work emails, and the question “Am I actually getting better?” While everyone’s story is unique,
certain themes often appear when people describe their experiences with esketamine plus oral antidepressants.

One common story starts with “I was doing everything right, but it still wasn’t enough.” Someone might
have tried several antidepressants over a span of years. Each time, there was initially some hopemaybe sleep
improved, maybe they cried lessbut the relief never felt stable. They’d have a few “good” weeks, only to find
themselves back in bed, scrolling their phone at 3 a.m., wondering why the medication seemed to have stopped working.

When esketamine enters the picture, the first sessions can feel strange. Many people describe the treatment time
as surreala bit like stepping into a dream where thoughts are more fluid, colors more vivid, or time feels
distorted. Some feel deeply relaxed; others feel a little uneasy at first. That’s why a calm, supportive clinic
environment and staff who explain what to expect can make a huge difference.

Over the following days, some people notice a subtle shift. They might say:

• “I still have problems, but they don’t feel as crushing.”
• “Getting out of bed is easier. Not easy, but easier.”
• “I actually caught myself laughing at something today, and that hasn’t happened in months.”

Importantly, many also talk about the way esketamine seems to help amplify the benefits of their existing antidepressant.
Instead of wild swingsthree good days, four bad daysthey may start to see a more consistent pattern of “okay”
days that slowly trend upward. In clinical terms, that’s moving from fluctuating response toward a more stable
response or sustained remission.

Families and friends often notice changes before the person does. A partner might point out, “You’ve been coming
to dinner more often,” or a friend might say, “You actually answered my text the same day I sent it!” Those
little markers of re-engagementgoing for a walk, showering regularly, showing up for a hobbyare often more
telling than any number on a depression scale.

There are also realistic frustrations. Some people find the side effects uncomfortabledizziness, nausea, or
feeling “weird” during and after sessions. Others find the schedule disruptive to work or caregiving responsibilities.
On top of that, navigating insurance approvals and clinic availability can feel like a part-time job.

Another common theme is that esketamine is not a standalone solution for life problems. People who get the
most out of it often use the “window” of improved mood and energy to lean into therapy, adjust unhelpful habits,
reconnect with supportive relationships, and address stressors where they can. Esketamine may help lift the fog;
it doesn’t file your paperwork, have that difficult conversation for you, or magically fix a toxic workplace.

There are also stories of non-response or partial response, where the hoped-for breakthrough doesn’t materialize
despite several sessions. These experiences are valid and can be deeply disappointing, especially after investing
time, emotion, and logistical effort. In those cases, teams often pivotre-examining the diagnosis, other medical
conditions, sleep disorders, substance use, or co-occurring anxiety, bipolar spectrum features, or trauma that might
require different strategies.

Overall, real-world experiences suggest that for some adults with fluctuating antidepressant response, adding
esketamine can help stabilize and deepen the improvements they get from oral medications. For others, it may offer
only a small benefit, or none at all. The key is that decisions about starting, continuing, or stopping esketamine
are made collaboratively, with careful monitoring and an honest look at how much it is moving the needle in daily life.

The Bottom Line

Esketamine nasal spray has added a new dimension to depression treatment by working through a different brain
pathway and, for some people, enhancing the effects of oral antidepressants. For adults whose symptoms bounce
up and down despite faithfully taking their medication, it offers a promising but carefully controlled option
to reduce symptom variability, deepen response, and, in some cases, maintain remission.

At the same time, esketamine is not a casual add-on. It requires in-clinic administration, close monitoring,
thoughtful screening, and ongoing conversations about benefits, risks, and life circumstances. It’s best understood
as one tool among manypowerful for some, less so for others, and always most effective when combined with
comprehensive, person-centered mental health care.

If fluctuating depression symptoms are making your life feel like an emotional roller coaster, the most important
next step is not to self-diagnose or self-treat, but to talk with a qualified mental health professional.
They can help you review past treatments, explore whether adjunctive options like esketamine make sense in your
specific situation, and build a plan that fits your needs, values, and safety.