JAMA Psychiatry
June 5, 2019
Ella J. Daly, Madhukar H. Trivedi, Adam Janik et al.
766 citations
For adults with treatment-resistant depression who achieved stable remission or response after 16 weeks of esketamine nasal spray plus an oral antidepressant, continuing esketamine plus the antidepressant delayed relapse significantly more than switching to placebo plus the antidepressant. Among those in stable remission, 26.7% relapsed on esketamine versus 45.3% on placebo, a 51% reduction in relapse risk. Among stable responders, 25.8% relapsed on esketamine versus 57.6% on placebo, a 70% reduction. Common side effects of esketamine included transient taste disturbance, vertigo, dissociation, drowsiness, and dizziness.
The International Journal of Neuropsychopharmacology
July 9, 2019
Maggie Fedgchin, Madhukar Trivedi, Ella J Daly et al.
593 citations
In a phase 3 trial of 346 adults with moderate-to-severe treatment-resistant depression, adding esketamine nasal spray (56 or 84 mg twice weekly) to a new oral antidepressant for 4 weeks did not significantly reduce depression scores compared to adding placebo nasal spray. The 84 mg dose failed to separate from placebo on the primary outcome, and the 56 mg dose could not be formally tested due to the statistical hierarchy. However, the magnitude of improvement with both esketamine doses exceeded what is typically considered clinically meaningful for approved antidepressants. Common side effects included nausea, dissociation, dizziness, vertigo, and headache. The authors conclude the results provide supportive evidence for esketamine's safety and efficacy in treatment-resistant depression.
Synapse
January 1, 1987
Pierre Blier, Claude de Montigny
428 citations
Rats given the 5-HT1A agonist gepirone for 14 days initially showed reduced firing of serotonin neurons in the dorsal raphe, which gradually returned to normal. After 14 days, the response of these neurons to intravenous LSD was markedly reduced, while responses to 8-OH-DPAT and gepirone were unchanged. Direct application of serotonin, LSD, 8-OH-DPAT, and gepirone to the neurons showed reduced responsiveness, but not to GABA. Postsynaptic hippocampal neurons remained normally responsive to serotonin and related drugs. The findings suggest that desensitization of somatodendritic 5-HT autoreceptors, combined with normal postsynaptic receptor activation, leads to increased tonic activation of postsynaptic 5-HT1A receptors, consistent with the delayed clinical anxiolytic and antidepressant effects of gepirone.
The Canadian Journal of Psychiatry
November 11, 2020
Jennifer Swainson, Alexander McGirr, Pierre Blier et al.
109 citations
A systematic review by the Canadian Network for Mood and Anxiety Treatments evaluated evidence for racemic ketamine in treatment-resistant depression. Single intravenous infusions have Level 1 evidence for efficacy in adults, while multiple or maintenance infusions have only Level 3 evidence. Adverse events include dissociative symptoms and hypertension. Non-IV formulations have Level 3 or 4 evidence. Single-dose IV racemic ketamine is a third-line recommendation; repeated use requires careful case-by-case risk-benefit assessment. Oral and other formulations should be limited to specialists with ketamine expertise at tertiary centers due to limited evidence and risk of misuse.
Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
The International Journal of Neuropsychopharmacology
March 1, 2003
Tarek Zghoul, Pierre Blier
13 citations
LSD enhances the inhibitory effect of serotonin on neurons in the orbitofrontal cortex, a brain region linked to obsessive-compulsive disorder (OCD), while reducing serotonin's inhibitory effect in the hippocampus, a region linked to depression. In rats under anesthesia, LSD applied directly to neurons decreased their firing rate and boosted serotonin's inhibitory action in the orbitofrontal cortex, but weakened it in the hippocampus. After four daily injections of LSD, the same pattern persisted 24 hours after the last dose, suggesting a lasting change in serotonin responsiveness. This enhancement in the orbitofrontal cortex may explain why some hallucinogens have anti-OCD effects that outlast their psychotomimetic action.
Journal of psychopharmacology (Oxford, England)
February 26, 2025
Sara de la Salle, Jennifer L Phillips, Pierre Blier et al.
3 citations
A sub-anesthetic dose of ketamine, an NMDAR antagonist, produces rapid antidepressant effects in treatment-resistant major depressive disorder. In 24 patients, ketamine reduced frontal mismatch negativity (MMN) amplitude, theta event-related oscillations, and source-localized frontal generator activity immediately and 2 hours after infusion, compared to midazolam. Larger reductions in MMN measures, particularly left frontal amplitude and theta oscillations, correlated with and predicted greater early and sustained symptom improvement on the Montgomery-Åsberg Depression Rating Scale. Baseline phase-locking factor also predicted sustained response. The findings suggest that acute NMDAR blockade reduces frontal MMN, and that MMN indices may serve as non-invasive biomarkers for predicting antidepressant response to glutamatergic agents.