Mechanism for the Antidepressant Effect of Ketamine Revealed

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Summary: Those with treatment-resistant depression showed significant improvement in symptoms and became more receptive to positive experiences after a one-week ketamine treatment.

Source: Paris Brain Institute

Researchers from Inserm, CNRS, Sorbonne University and clients from the AP-HP and at the Paris Brain Institute identified one of the mechanisms that explain the effect of ketamine as an antidepressant.

Ketamine, commonly used as an anesthetic, was administered to patients with severe resistant depression. This treatment leads patients to present an increased ability to overcome their negative beliefs about themselves and the world when researchers present them with positive information.

These results, published in JAMA Psychiatry, open new therapeutic avenues for the management of antidepressant-resistant mood disorders.

Depression is the most common psychiatric disorder: it is estimated that 5 to 15% of the French population will experience a major depressive episode in their lifetime. All age groups and all social backgrounds are affected.

The disease is characterized by sadness and loss of hedonic feelings that positive events do not improve. Depressed patients gradually develop negative beliefs about themselves, the world and the future, which can develop into suicidal thoughts. These negative beliefs remain even when the patient receives positive information.

About a third of people with depression do not respond to the most commonly prescribed antidepressants, leading to a diagnosis of treatment-resistant depression (TRD). For these people, finding new and effective therapies is a priority.

Ketamine, a commonly used anesthetic, has been shown to affect resistant depression. While conventional antidepressant treatments take time to be effective (three weeks on average), ketamine has a rapid antidepressant effect, just a few hours after administration. The mechanisms associated with this fast-acting antidepressant effect are still unknown.

To identify these mechanisms, Dr. Hugo Bottemanne and the research team jointly led by the Paris Brain Institute by Pr Philippe Fossati and Liane Schmidt, Inserm researcher, coordinated a clinical study involving 26 antidepressant-resistant patients (TRD) and 30 healthy controls.

During the protocol, patients and healthy subjects were first asked to estimate the probability of 40 “negative” events that could occur in their lives (for example, having a car accident, getting cancer, or losing their wallet).

After being informed about the actual risks of occurrence in the general population, patients and healthy subjects were again asked to estimate the probability of these events occurring in their lifetime. The research team was interested in updating beliefs after obtaining information.

Ketamine, a commonly used anesthetic, has been shown to affect resistant depression. Image is in the public domain

Results showed that healthy subjects tended to update their initial beliefs more after receiving factual and positive information, which was not the case in the depressed patient population.

In the suite of the study, TRD patients received three administrations of ketamine at a subanesthetic dose (0.5 mg/kg over 40 minutes) in one week.

Only four hours after the first administration, the ability of patients to update their beliefs after receiving a positive information was increased. They became less sensitive to negative information and gained an ability to compare their knowledge with that of control subjects.

Moreover, improvement in depressive symptoms after ketamine treatment was associated with these changes in belief updating, suggesting a link between clinical improvement and changes in this cognitive mechanism. “In other words, the more the patient’s ability to update beliefs was increased, the greater was the improvement in symptoms.”

Finally, in this study, patients with antidepressant-resistant depression showed a significant decrease in symptoms and became more receptive to “positive” experiences after one week of ketamine treatment.

This work highlights for the first time a cognitive mechanism that may be involved in the early effect of ketamine. It paves the way for new research into antidepressant therapies that modulate the mechanisms of belief updating.

About this news about psychopharmacological research

Writer: Nicholas Brad
Source: Paris Brain Institute
Contact: Nicolas Brard – Paris Brain Institute
Image: The image is in the public domain

Original research: Free access.
“Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression” by Hugo Bottemanne et al. JAMA Psychiatry


Evaluation of early ketamine effects on belief-updating biases in patients with treatment-resistant depression


Clinical research has shown that persistent negative beliefs maintain depression and that subanesthetic ketamine infusions induce rapid antidepressant responses.

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To evaluate whether ketamine changes the actualization of beliefs and how such cognitive effects are associated with the clinical effects of ketamine.

Design, setting and participants

This study used an observational case-control protocol with a mixed-effects design that nested 2 groups at 2 testing time points. Observers were not blinded. Patients with treatment-resistant depression (TRD) and healthy volunteer participants aged 34 to 68 years were included. Patients with TRD were diagnosed with major depressive disorder or bipolar depression, had a Montgomery-Åsberg Depression Rating Scale score greater than 20, a Maudsley Staging Method score greater than 7, and failed to respond to at least 2 prior antidepressant trials . Exclusion criteria were any other psychiatric, neurological, or neurosurgical comorbidities, substance use or addictive disorders, and recreational ketamine consumption. Data was collected from January to February 2019 and from May to December 2019, and data was analyzed from January 2020 to July 2021.


Patients with TRD were assessed 24 hours before a single ketamine infusion, 4 hours after the infusion, and 4 hours after the third infusion, which was 1 week after the first infusion. Healthy control participants were observed twice 1 week apart without ketamine exposure.

Main outcomes and measures

Montgomery-Åsberg Depression Rating Scale score and belief updating after belief updating when patients received good news and bad news, measured by a cognitive belief updating task and mathematically formalized by a computational reinforcement learning model.


Of the 56 participants included, 29 (52%) were male, and the mean (SEM) age was 52.3 (1.2) years. A total of 26 patients with TRD and 30 control participants were included. A significant group × test time point × news valence interaction showed that patients with TRD updated their beliefs more toward good than bad news after a single ketamine infusion (controlled for age and education: β = −0.91; 95% CI, −1.58 to − 0.24; t216= -2.67; P= .008) than controls. Computational modeling showed that this effect was associated with asymmetric learning rates (LRs) after ketamine treatment (good news LRs after ketamine, 0.51 [SEM, 0.04]; bad news LRs to ketamine 0.36 [SEM, 0.03], t25= 3.8; P<.001) and partially mediated early antidepressant responses (path a*b: β = −1.00 [SEM, 0.66]; t26= -1.53; z= -1.98; P= .04).

Conclusions and relevance

These findings provide new insights into the cognitive mechanisms of action of ketamine in patients with TRD, with promising perspectives for enhanced psychotherapy for individuals with mood disorders.

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