Hugo Bottemanne1,2,3, Orphee Morlaas1, Anne Claret2, Tali Sharot4,5,6, Philippe Fossati1,2, Liane Schmidt1. 1. Control-Interoception Attention Team, Paris Brain Institute, Sorbonne University, National Institute of Health and Medical Research, French National Centre for Scientific Research, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, DMU Neuroscience, Paris, France. 2. Department of Psychiatry, Pitié-Salpêtrière Hospital, DMU Neuroscience, Sorbonne University, Assistance Publique-Hôpitaux de Paris, Paris, France. 3. Department of Philosophy, Sorbonne University, SND Research Unit, UMR 8011, Paris, France. 4. Affective Brain Lab, Department of Experimental Psychology, University College London, London, United Kingdom. 5. Max Planck UCL Centre for Computational Psychiatry and Ageing Research, London, United Kingdom. 6. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
Abstract
Importance: Clinical research has shown that persistent negative beliefs maintain depression and that subanesthetic ketamine infusions induce rapid antidepressant responses. Objective: To evaluate whether ketamine alters belief updating 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 by 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 were collected from January to February 2019 and from May to December 2019, and data were analyzed from January 2020 to July 2021. Exposures: Patients with TRD were observed 24 hours before 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. Results: Of 56 included participants, 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 × testing time point × news valence interaction showed that patients with TRD updated their beliefs more after good than bad news following 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 asymmetrical learning rates (LRs) after ketamine treatment (good news LRs after ketamine, 0.51 [SEM, 0.04]; bad news LRs after 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 novel insights into the cognitive mechanisms of the action of ketamine in patients with TRD, with promising perspectives for augmented psychotherapy for individuals with mood disorders.
Importance: Clinical research has shown that persistent negative beliefs maintain depression and that subanesthetic ketamine infusions induce rapid antidepressant responses. Objective: To evaluate whether ketamine alters belief updating 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 by 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 were collected from January to February 2019 and from May to December 2019, and data were analyzed from January 2020 to July 2021. Exposures: Patients with TRD were observed 24 hours before 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. Results: Of 56 included participants, 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 × testing time point × news valence interaction showed that patients with TRD updated their beliefs more after good than bad news following 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 asymmetrical learning rates (LRs) after ketamine treatment (good news LRs after ketamine, 0.51 [SEM, 0.04]; bad news LRs after 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 novel insights into the cognitive mechanisms of the action of ketamine in patients with TRD, with promising perspectives for augmented psychotherapy for individuals with mood disorders.
Authors: Tobias Kube; Winfried Rief; Mario Gollwitzer; Thomas Gärtner; Julia Anna Glombiewski Journal: Psychol Med Date: 2018-08-22 Impact factor: 7.723
Authors: Tali Sharot; Ryota Kanai; David Marston; Christoph W Korn; Geraint Rees; Raymond J Dolan Journal: Proc Natl Acad Sci U S A Date: 2012-09-24 Impact factor: 11.205