- Christopher Dull
- Nov 13
- 3 min read
Updated: Nov 20
To begin — we only know some of the story
It’s really important to know that the most accurate answer to any "how and why" questions about psychiatric medicine is basically “we don’t know for sure,” to be followed by “our current understanding is….” The science has advanced, but the "how" and "why" cannot be answered conclusively. We simply don’t possess that level of knowledge.
How we thought antidepressants worked (and what we know now)
For many years, the leading idea (by far) was that antidepressants worked mainly by keeping certain neurotransmitters—especially serotonin and norepinephrine—available a little longer in the space between nerve cells (the synaptic cleft). The assumption was that more neurotransmitter in the cleft meant more activation of receptors on the receiving neuron, correcting a presumed deficiency. In other words, there weren't enough neurotransmitters like serotonin to fully signal the next neuron, and if certain neurons didn't get enough serotonin, depression would start.
More recent, comprehensive reviews of the literature call into question this model. We do see increases in synaptic neurotransmitter availability from these medicines, but whether that change by itself explains clinical improvement is uncertain. The field has shifted toward models emphasizing that certain conditions (including medicines and talk therapy) may trigger adaptations (receptor changes, different neuron to neuron signaling, and neuroplasticity) that unfold over weeks. It is believed that these changes lead collectively to improvements in problematic psychiatric conditions.
The good news: the treatments work
Antidepressants—including ketamine and esketamine—have been shown to help many people in randomized, controlled trials. These studies compare treatment with these medicines and a separate placebo (or active control) group. The patients and raters are blinded to which substance is used. For positive findings to be accepted, they must show any benefit is statistically meaningful rather than due to chance. Repeatedly, the studies show these medicines work—even if we don't know exactly why.
Why skepticism is good
It’s important to approach bold claims with a bit of skepticism. You’ll see many explanations for “how ketamine works”; some go beyond what the data support. Our goal is to be both hopeful and accurate—neither over-promising nor failing to accurately report very promising benefits.
How ketamine and esketamine may work faster (short version)
Traditional antidepressants (including SSRIs, SNRIs, TCAs, and MAOIs) may start altering serotonin/norepinephrine systems and then trigger slower downstream changes—neuroplasticity—that often take 2–8+ weeks to reach their lasting benefit. Patients can notice early improvements, but the larger gains usually take time.
By contrast, ketamine and esketamine seem to start in a different place. Rather than working mainly through serotonin, they briefly shift signaling with glutamate—another brain messenger. This appears to open a short window when the brain can rewire more easily, which lines up with the hours-to-days improvements seen in clinical studies.
How fast is “fast,” realistically?
Some patients notice improvements the same day; many notice changes within 24–72 hours after a treatment. Improvements can include significant relief of depressive symptoms and, in some studies, reductions in suicidal thoughts—particularly with IV ketamine. This is faster than what we typically observe with standard oral antidepressants, where clear benefits more often build over weeks.
More detailed information
Important context to know first
Most ketamine/esketamine trials below enrolled people with treatment-resistant depression (TRD). Your experience and outcome may differ if you’re not in that specific group.
In any clinical study, some people improve even without the active medicine (the placebo effect or simply getting better over time). Keep that in mind when you look at percentages, because the placebo response was variable from study to study. That said, in all of these examples, the outcomes listed were statistically significant (<5% likelihood the difference was due to chance).
Comparative timing for ketamine, esketamine, and traditional antidepressants
24–48 hours
IV ketamine: About 64% responded by 24 hours.
Intranasal esketamine while also taking an oral antidepressant: By ~48 hours, roughly 17% met response criteria.
Oral antidepressants: Rare to achieve a full response this early; the first meaningful improvement often begins around week 1.
Week 1
IV ketamine: After a single infusion, many people who improve in the first day are still better at one week; across studies, roughly 35–40% still meet response criteria at Day 7.
Esketamine: More patients begin to respond significantly as doses add up.
Oral antidepressants: The first clear improvement is often noticeable by about week 1, though many people still have modest (not robust) changes at that point.
Weeks 2–4 (end of "induction" phase)
IV ketamine: ~60–70% by 2–3 weeks (after generally 6 treatments).
Esketamine + oral antidepressant: ~46–61% respond at Day 28 (after about 8 treatments).
Oral antidepressants: At 4 weeks, many are still improving; by 6–8 weeks, about 50% respond.
Thank you for reading. More ketamine/esketamine information to follow soon . . .
Please remember that the medical information on this page is educational and not a substitute for personalized medical advice.