Archives of General Psychiatry
August 1, 2010
Nancy Diazgranados, Lobna Ibrahim, Nancy E. Brutsché et al.
969 citations
A single intravenous dose of ketamine, an N-methyl-D-aspartate-receptor antagonist, produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. Depressive symptoms improved within 40 minutes and remained significantly better than placebo through day 3. The largest drug effect occurred at day 2. Seventy-one percent of subjects responded to ketamine versus 6% to placebo. One subject in each group developed manic symptoms. Ketamine was generally well tolerated, with dissociative symptoms only at the 40-minute point.
Harvard Review of Psychiatry
August 1, 2010
Carlos A. Zarate, Rodrigo Machado‐Vieira, Ioline D. Henter et al.
226 citations
Mood disorders like bipolar disorder and major depressive disorder are common, chronic, and recurrent, affecting millions worldwide. Existing antidepressants and mood stabilizers are insufficient for many, with low remission rates, delayed action, residual symptoms, and relapses. New therapeutic agents with faster and sustained effects are urgently needed. The glutamatergic system has been implicated in the pathophysiology of these disorders, with evidence confirming the role of modulators riluzole and ketamine as proof-of-concept agents. Trials with diverse glutamatergic modulators are underway, and this system holds promise for developing next-generation therapeutics.
The International Journal of Neuropsychopharmacology
November 1, 2011
Giacomo Salvadore, Jan Willem van der Veen, Yan Zhang et al.
105 citations
Pretreatment levels of certain amino-acid neurotransmitters in the prefrontal cortex predict how well patients with major depressive disorder respond to a single intravenous infusion of ketamine. In fourteen drug-free patients, a lower ratio of glutamine to glutamate in the dorsomedial/dorsal anterolateral prefrontal cortex was associated with greater improvement in depressive symptoms 230 minutes after ketamine administration. Higher glutamate levels in the ventromedial prefrontal cortex correlated with greater improvement in anxiety symptoms. The findings suggest that the presence of reduced glial cells, reflected by the lower glutamine-to-glutamate ratio, may indicate which patients are more likely to benefit from ketamine treatment.
Translational Psychiatry
September 20, 2016
Daniel M. Rotroff, Daniel Corum, Alison A. Motsinger‐Reif et al.
99 citations
Sub-anesthetic doses of ketamine and its S-enantiomer, esketamine, rapidly reduce depression symptoms in patients with treatment-resistant major depressive disorder. A pharmacometabolomics approach mapped global metabolic effects in 33 patients receiving ketamine and 20 receiving esketamine, with esketamine retested after a second infusion four days later. Both drugs altered metabolites related to tryptophan metabolism (e.g., indole-3-acetate and methionine) and the urea cycle (e.g., citrulline, arginine, and ornithine) two hours post-infusion. Changes in glutamate and circulating phospholipids were significantly associated with decreases in depression severity. These findings provide new insights into the mechanisms underlying the rapid antidepressant effects of these therapies.
CNS Neuroscience & Therapeutics
April 12, 2013
Giacomo Salvadore, Jaskaran Singh
80 citations
A single intravenous subanesthetic dose of ketamine, an NMDA receptor antagonist, rapidly reduces depressive symptoms and suicidal thoughts in patients with treatment-resistant mood disorders. Emerging evidence suggests that ketamine's antidepressant effects depend on increasing AMPA signaling and rapidly inducing synaptogenesis. However, critical questions remain about safe and effective use, including optimal dose, administration method, and biomarkers of response. This review summarizes clinical evidence, preclinical and human studies on ketamine's mechanisms and predictors of antidepressant response, and identifies knowledge gaps to guide future research toward developing more effective, fast-acting antidepressants.
The Journal of Clinical Psychiatry
July 16, 2021
Ibrahim Turkoz, Ella Daly, Jaskaran Singh et al.
21 citations
For patients with treatment-resistant depression who did not show a response within the first week of treatment, a full four-week induction course of esketamine nasal spray plus an oral antidepressant may still provide benefit. In a pooled analysis of two phase 3 trials, among those not meeting early response criteria at day 2 or days 2 and 8, the odds of a response by day 28 were about 1.6 times higher with esketamine plus antidepressant compared to antidepressant plus placebo. The findings suggest that lack of early improvement does not preclude later benefit from the full induction course.
Psychiatry Research
March 15, 2023
Ibrahim Turkoz, J. Craig Nelson, Samuel T. Wilkinson et al.
19 citations
A post hoc analysis of two pooled 4-week phase 3 trials examined predictors of response and remission in patients with treatment-resistant depression receiving esketamine nasal spray plus a new oral antidepressant compared to a new oral antidepressant plus placebo nasal spray. Younger age, being employed, having fewer failed antidepressants in the current episode, and early reduction in Clinical Global Impression-Severity score at day 8 predicted better outcomes. Those on esketamine had 68% higher odds of response and 55% higher odds of remission. In the esketamine group, response was more likely in employed patients, those without baseline anxiety, and those with early symptom improvement.
CNS Spectrums
July 29, 2022
Ibrahim Turkoz, Oliver Lopena, Giacomo Salvadore et al.
6 citations
In adults with major depressive disorder and active suicidal ideation with intent who did not show early improvement, adding esketamine nasal spray to standard care increased the likelihood of achieving a response (63.9% vs 48.0%) and remission (35.1% vs 24.4%) after four weeks compared to placebo plus standard care. The odds of response were nearly double with esketamine. Similar benefits appeared for those who had not responded after one week. The findings suggest that continuing esketamine treatment for the full four weeks can be beneficial even when early response is absent.