Ketamine Therapy Research Summary (2020–2024)

A public summary of my open-access white paper reviewing 25 systematic reviews (2020–2024).

This page has been medically reviewed by a board-certified psychiatrist with clinical experience in mood disorders on November 21, 2025.

Ketamine Therapy Research Summary

13 essential insights from 25 systematic reviews (2020–2024)

1

The hierarchy across pooled evidence: IV ketamine produces the largest short-term antidepressant signal. Spravato produces substantial clinical response/remission during induction, while showing a smaller “drug-specific lift” above placebo in meta-analysis. Oral ketamine shows the weakest evidence profile.

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Meaning: Achieving up to ~43% remission after only 1–2 infusions is rare in treatment-resistant depression. Even the lower end of these pooled ranges is well above typical antidepressant remission benchmarks, and it happens on a rapid time course.

3

Meaning: Clinically, Spravato induction produces high real-world-relevant remission and response ranges across pooled reviews. It is not a weak treatment; it’s a legitimately strong antidepressant option for many patients.

Meaning: When analysts subtract the very large placebo improvement seen in ketamine trials, the extra lift attributable to esketamine alone looks modest. That modest incremental lift can coexist with strong clinical remission rates.

4

Bottom line of the paradox: Spravato generates strong clinical response/remission during induction, yet the drug’s incremental advantage over placebo is smaller once huge placebo gains and long trial timelines are accounted for. Both statements are true because they answer different statistical questions.

5

Meaning: In systematic-review evidence through 2024, oral/sublingual ketamine remains a lower-certainty option: it may help some patients, but it does not show the strong, rapid, reproducible remission profile seen with IV ketamine or the strong clinical induction results seen with Spravato.

6

Durability is still the weak spot of the pooled literature—especially for IV ketamine—because long, standardized protocols haven’t yet generated enough systematic-review data to pin down long-term remission rates with confidence.

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For IV ketamine, controlled trials report around ~63% response, while real-world clinic data average closer to ~30% response—still meaningful, but more conservative than trial headlines.

9

The white paper catalogued systematic reviews/meta-analyses (Jan 2020–Dec 2024) on ketamine for depression only, excluding reviews centered on PTSD, chronic pain, anxiety, addiction, or other indications. Routes included IV/IM racemic ketamine, esketamine nasal spray, oral/sublingual ketamine, and ketamine-assisted psychotherapy combinations.

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Alvear, M. (2025). Systematic Reviews and Meta-Analyses of Ketamine Therapy: 25 Studies | 2020–2024 | Comparative Evidence Summary. KetamineTherapyForDepression.org. https://doi.org/10.5281/zenodo.15196895

13

1. Why do Spravato studies show high response and remission rates, yet placebo-controlled reviews say the drug’s added benefit is modest?

Because those two results are measuring different things. In longer Spravato induction studies and in systematic reviews that summarize real clinical courses, many patients improve a lot: about 49–77% show a major symptom drop and about 32–58% reach remission during induction. But ketamine trials also have unusually strong placebo improvement—so when analysts compare Spravato to placebo, the extra benefit that is clearly attributable to the drug alone comes out smaller. Both facts can be true at once: Spravato has strong clinical outcomes, and yet placebo arms improve so much that the drug’s “above-placebo” slice looks modest.

2. What do “response” and “remission” mean in the studies summarized in this paper?

“Response” means a clinically meaningful improvement—typically defined as at least a 50% reduction in depression symptoms on standard rating scales. “Remission” is a higher bar: symptoms become minimal or essentially disappear, so the person is no longer meeting criteria for an active depressive episode. In other words, response = big improvement; remission = close to well.

3. Are the IV ketamine remission numbers mostly based on one or two infusions, or on longer multi-infusion series?

Mostly one or two infusions. Across pooled reviews, about 27–43% of patients reach remission after IV ketamine, and the underlying studies driving those numbers overwhelmingly measure outcomes after just 1–2 treatments. Some reviews mention higher remission in short multi-infusion series, but they rarely specify exact infusion counts and still lean heavily on short-protocol data. So the striking point is: IV ketamine shows unusually high remission early, while long-protocol remission and durability are still under-studied in systematic reviews.

4. How quickly do people typically feel better in the IV, Spravato, and oral studies summarized here?

IV ketamine is the fastest in the pooled depression literature: many patients show relief within hours and clearly within 24 hours of a single infusion. Spravato is also rapid but typically a bit slower than IV; effects commonly begin within about 2–4 hours of dosing. Oral/sublingual ketamine is the slowest route in the reviews, with meaningful improvement usually appearing after roughly 2–6 weeks of repeated dosing.

5. How large is the placebo effect in ketamine trials, and how should readers interpret the results knowing that?

Systematic reviews estimate that placebo and other non-specific factors account for roughly 62–78% of the total symptom improvement seen in ketamine trials—much higher than in most psychiatric drug studies. This doesn’t mean ketamine “doesn’t work.” It means the clinical setting, expectations, and study design amplify improvement in both drug and placebo groups. The right interpretation is: ketamine still adds real benefit, especially IV ketamine, but raw remission/response numbers should be read with the understanding that placebo improvement is unusually strong in this field.

6. Why do independent systematic reviews often report smaller Spravato benefits than manufacturer-run trials?

Independent reviews usually apply stricter pooling rules and are less influenced by how trial results are framed in sponsor publications. Many major Spravato trials were industry-sponsored, and independent reviewers tend to re-analyze the same bodies of data more conservatively. That doesn’t automatically mean sponsor trials are “wrong,” but it does mean independent summaries often land on smaller, more cautious estimates of how much Spravato outperforms placebo.

7. What are the biggest evidence gaps or weaknesses across the ketamine routes covered in this paper?

The main gaps are about long-term durability and standardization. For IV ketamine, most pooled remission/response numbers come from short protocols (1–2 infusions), so systematic reviews still can’t firmly quantify remission after full standardized infusion series or how long remission lasts without maintenance. For oral ketamine, the evidence base is thinner, more heterogeneous in dosing and monitoring, and has not produced a robust remission signal. For Spravato, the evidence is stronger clinically, but placebo effects and sponsorship patterns make “added-benefit above placebo” estimates smaller and more debated.

8. How should readers use these findings without assuming the numbers apply to every individual or every clinic protocol?

Treat these results as pooled averages from controlled research, not guarantees. Real-world clinics often see lower response rates than tightly controlled trials, and protocols vary in dose, spacing, and patient selection. The findings are best used to set realistic expectations and compare routes on the same playing field—while recognizing that individual outcomes can be better or worse depending on diagnosis, protocol quality, and follow-up care.