Key Takeaways
- A JAMA Psychiatry study found that people with treatment-resistant depression showed changes in how they updated negative beliefs as early as four hours after their first ketamine infusion (Bottemanne et al., 2022).
- The study included 26 patients with treatment-resistant depression and 30 healthy participants and was observational rather than a randomized, placebo-controlled clinical trial.
- After one week, changes in belief updating were associated with the clinical antidepressant response, suggesting a possible connection between ketamine’s cognitive and antidepressant effects (Bottemanne et al., 2022).
- The findings do not prove that changing negative beliefs causes ketamine’s antidepressant effects.
- Ketamine is FDA-approved as an anesthetic but is not FDA-approved for depression or other psychiatric disorders. Ketamine may nevertheless be prescribed off-label for depression. Esketamine, a related drug, is FDA-approved for treatment-resistant depression in adults (U.S. Food and Drug Administration [FDA], 2026).
- Ketamine treatment is not appropriate for everyone and should be considered with a qualified healthcare professional who can evaluate its potential benefits and risks.
Depression can affect the way people feel, think, and function in everyday life. For some patients, symptoms persist despite multiple treatment attempts, creating a need for additional therapeutic options.
Ketamine
One area attracting considerable scientific attention is ketamine.
Research published in JAMA Psychiatry suggests that ketamine may rapidly change how some people with treatment-resistant depression process negative beliefs. In the study, changes in belief updating appeared as early as four hours after the first ketamine infusion and were associated with improvement in depressive symptoms after one week (Bottemanne et al., 2022).
The results offer a potential clue to understanding the rapid cognitive effects associated with ketamine treatment. However, the study was small and observational. It therefore cannot establish that changes in negative beliefs are the mechanism responsible for ketamine’s antidepressant effects.
What Is Treatment-Resistant Depression?
Depression, also called major depressive disorder or clinical depression, is more than occasionally feeling sad or discouraged. It can cause persistent symptoms that interfere with a person’s thoughts, emotions, sleep, appetite, work, relationships, and other daily activities (National Institute of Mental Health [NIMH], n.d.-a).
Depression is also common. NIMH estimates based on the 2021 National Survey on Drug Use and Health indicate that approximately 21 million U.S. adults, or 8.3% of the adult population, experienced at least one major depressive episode during the previous year (NIMH, n.d.-b).
Symptoms vary from person to person and may include persistent sadness or emptiness, hopelessness, loss of interest or pleasure, feelings of worthlessness, fatigue, difficulty concentrating, changes in sleep or appetite, and thoughts of death or suicide (NIMH, n.d.-a).
Treatment commonly involves psychotherapy, medication, or a combination of approaches. Some people, however, continue to experience significant symptoms despite treatment.
In the JAMA Psychiatry study, the researchers included patients with treatment-resistant depression who had failed to respond to at least two previous antidepressant trials (Bottemanne et al., 2022).
Why Researchers Studied Negative Beliefs
Depression does not affect mood alone. It can also influence how people interpret information about themselves and what they expect from the future.
People with depression may, for example, have difficulty revising negative expectations even when they receive unexpectedly positive information. Researchers have consequently become interested in whether changes in this type of information processing accompany improvement in depression.
Bottemanne et al. (2022) investigated whether ketamine could affect this process, known as belief updating, in patients with treatment-resistant depression.
Rather than simply asking whether patients felt better after ketamine, the researchers examined whether treatment was associated with measurable changes in the way patients incorporated new information into their expectations.
This distinction is important because the study was investigating a possible cognitive process associated with ketamine’s rapid effects rather than simply testing whether ketamine works as an antidepressant.
How the Ketamine Study Was Conducted
The observational case-control study involved 56 participants between the ages of 34 and 68. Of these, 26 had treatment-resistant depression, and 30 were healthy control participants (Bottemanne et al., 2022).
Patients in the treatment-resistant depression group had major depressive disorder or bipolar depression and had failed to respond adequately to at least two previous antidepressant treatments.
The patients received three intravenous ketamine infusions over one week. The second infusion was administered 48 hours after the first, and the third was given five days after the first infusion.
Researchers assessed participants before treatment and again after ketamine administration.
To investigate belief updating, participants estimated their likelihood of experiencing different adverse life events. They were subsequently shown information about the actual probability of those events occurring in the general population.
Researchers could then examine how participants changed their expectations after receiving information that was either better or worse than they had anticipated.
Changes Appeared Four Hours After the First Ketamine Infusion
The researchers found that patients with treatment-resistant depression showed changes in how they incorporated favorable information into their beliefs following ketamine treatment.
An optimism bias in belief updating was detectable four hours after the first ketamine infusion (Bottemanne et al., 2022).
In practical terms, patients became more likely to update their expectations in response to unexpectedly favorable information.
After one week of treatment, the magnitude of this change was associated with the clinical antidepressant response. Patients who demonstrated greater changes in belief updating also tended to experience greater improvement in depressive symptoms (Bottemanne et al., 2022).
The finding raises the possibility that changes in information processing could be connected to ketamine’s rapid antidepressant effects.
However, an association is not the same as proof of causation. The study cannot establish that more optimistic belief updating caused patients’ depression to improve.
What Could the Findings Mean?
The study provides researchers with another possible avenue for investigating why ketamine can produce rapid clinical changes in some patients with difficult-to-treat depression.
Traditional antidepressants can take time to produce noticeable benefits. Ketamine has generated interest partly because clinical improvement may occur considerably faster in some patients.
The belief-updating findings suggest that measurable cognitive changes may also emerge rapidly.
This does not mean that ketamine simply makes a person “think positively.” Belief updating is a specific cognitive process that researchers can measure experimentally, and the relationship between that process and depression is considerably more complex than replacing negative thoughts with positive ones.
The results instead suggest that ketamine may be associated with changes in how patients incorporate new information when forming expectations.
Further research is needed to determine whether this cognitive change contributes directly to clinical improvement, occurs alongside improvement, or reflects another underlying process.
Ketamine Is Not the Same as Esketamine
An important distinction for patients is the difference between ketamine and esketamine.
Ketamine is an established anesthetic and a Schedule III controlled substance in the United States. Although clinicians may prescribe ketamine off-label for depression, ketamine itself is not FDA-approved for the treatment of depression or any other psychiatric disorder (FDA, 2026).
Esketamine is related to ketamine but is a distinct medication. FDA-approved esketamine is marketed as Spravato and administered as a nasal spray. It is approved for certain adults with treatment-resistant depression and for depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior (FDA, 2025).
Esketamine also carries important safety requirements. Because of risks including sedation, dissociation, respiratory depression, abuse, and misuse, Spravato is subject to a Risk Evaluation and Mitigation Strategy (REMS) and is administered under medical supervision (FDA, 2026).
Patients should therefore not interpret research involving medically supervised intravenous ketamine as evidence supporting unsupervised ketamine use.
How Does Ketamine Compare With Other Treatments?
Ketamine is not the only treatment considered for severe or difficult-to-treat depression. Electroconvulsive therapy (ECT), for example, has long been used for certain severe depressive episodes.
A 2022 systematic review and meta-analysis published in JAMA Psychiatry compared ketamine with ECT across six clinical trials involving 340 patients with major depressive episodes. The analysis suggested that ECT may have greater acute efficacy for reducing depression severity, although ketamine and ECT had different adverse-effect profiles (Rhee et al., 2022).
The authors emphasized that treatment decisions should be individualized and account for factors including potential adverse effects and patient preferences (Rhee et al., 2022).
These findings provide useful context for the belief-updating study. Ketamine is a promising area of depression research, but evidence does not support viewing it as a universal replacement for established treatments.
Important Limitations of the Study
The findings from Bottemanne et al. (2022) should be interpreted cautiously.
First, the study was small. Only 26 patients with treatment-resistant depression received ketamine.
Second, it was an observational case-control study rather than a randomized, placebo-controlled trial. Observers were also not blinded.
Third, patients continued their usual antidepressant medications during the study. This makes it more difficult to isolate every effect attributable specifically to ketamine.
Fourth, the study followed treatment over only one week. It therefore cannot tell us whether the changes in belief updating persist over months or whether they predict long-term remission.
Finally, an association between belief updating and improvement in depressive symptoms does not demonstrate that one caused the other.
These limitations do not make the findings unimportant. They mean that the results should be treated as evidence supporting further investigation rather than definitive proof of how ketamine produces its antidepressant effects.
What Patients Should Know About Ketamine for Depression
The study adds to research examining the rapid effects of ketamine in people whose depression has not responded adequately to conventional treatment.
It does not mean that ketamine is appropriate for every person with depression.
Ketamine is a prescription controlled substance with medical risks and should be administered or prescribed only after an appropriate clinical evaluation. Patients interested in ketamine or esketamine should discuss their symptoms, treatment history, other medications, medical conditions, potential adverse effects, and available alternatives with a qualified healthcare professional.
People should also distinguish between supervised medical treatment and recreational or unsupervised ketamine use. Findings from controlled clinical settings should not be interpreted as evidence that self-treatment with ketamine is safe or effective.
Related Reading:
Contrary to Common Belief, the Risk of Addiction to Ketamine Is Low
McGill University Study Shows How Ketamine Treats Severe Forms of Depression
Ketamine Can Switch off the Brain in an Instant
Psilocybin Shows Gender-Specific Effects on CNS Reactivity and Behavioral Responses
Final Thoughts
The JAMA Psychiatry study offers an intriguing look at what may happen cognitively soon after ketamine treatment. Researchers observed changes in belief updating just four hours after the first infusion in patients with treatment-resistant depression, and those changes were associated with clinical improvement after one week (Bottemanne et al., 2022).
What the study does not show is equally important. It does not prove that changing negative beliefs causes ketamine’s antidepressant effects, establish ketamine as superior to other treatments, or demonstrate that every patient with treatment-resistant depression will benefit.
Instead, the findings provide a possible piece of the larger puzzle surrounding ketamine’s rapid effects on depression. Larger randomized and controlled studies with longer follow-up will be necessary to determine how belief updating relates to treatment response and whether understanding this cognitive process can ultimately help clinicians improve outcomes for patients with difficult-to-treat depression.
For patients, the practical message is straightforward: ketamine research is promising, but treatment decisions should be based on an individual’s diagnosis, medical history, previous treatment response, potential risks, and guidance from an appropriately qualified healthcare professional.
References
Bottemanne, H., Morlaas, O., Claret, A., Sharot, T., Fossati, P., & Schmidt, L. (2022). Evaluation of early ketamine effects on belief-updating biases in patients with treatment-resistant depression. JAMA Psychiatry, 79(11), 1124–1132. https://doi.org/10.1001/jamapsychiatry.2022.2996
National Institute of Mental Health. (n.d.-a). Depression. U.S. Department of Health and Human Services. https://www.nimh.nih.gov/health/topics/depression
National Institute of Mental Health. (n.d.-b). Major depression. U.S. Department of Health and Human Services. https://www.nimh.nih.gov/health/statistics/major-depression
Rhee, T. G., Shim, S. R., Forester, B. P., Nierenberg, A. A., McIntyre, R. S., Papakostas, G. I., Krystal, J. H., Sanacora, G., & Wilkinson, S. T. (2022). Efficacy and safety of ketamine vs electroconvulsive therapy among patients with major depressive episode: A systematic review and meta-analysis. JAMA Psychiatry, 79(12), 1162–1172. https://doi.org/10.1001/jamapsychiatry.2022.3352
U.S. Food and Drug Administration. (2026, June 23). All Ketamine HCL / www.allketaminehcl.com – 725150 – 06/23/2026.
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/all-ketamine-hcl-wwwallketaminehclcom-725150-06232026
U.S. Food and Drug Administration. (2025). Spravato (esketamine) nasal spray, CIII: Highlights of prescribing information.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/211243s016lbl.pdf
