The Journal of Clinical Psychiatry
July 13, 2010
Nancy Diazgranados, Lobna Ibrahim, Nancy E. Brutsché et al.
563 citations
A single infusion of ketamine (0.5 mg/kg) rapidly reduced suicidal thoughts in people with treatment-resistant major depression. Suicidal ideation scores dropped significantly within 40 minutes and remained lower for at least 4 hours. Among the 10 participants who had a score of 4 or higher on the Scale for Suicide Ideation at the start, all dropped below 4—9 within 40 minutes and 1 by 80 minutes. Depression, anxiety, and hopelessness also improved substantially at all measured time points. The findings suggest ketamine may offer a fast-acting intervention for suicidal ideation, a medical emergency with few pharmacologic options.
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.
Therapeutic Advances in Chronic Disease
April 13, 2015
Nicolas D. Iadarola, Mark J. Niciu, Erica M. Richards et al.
202 citations
A single subanesthetic dose infusion of the noncompetitive NMDA receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression, unlike current monoaminergic antidepressants which have a delayed onset and limited efficacy. Preclinical studies inspired by ketamine's clinical effects reveal enhanced synaptic plasticity and synaptogenesis through mechanisms including release of local translational inhibition of brain-derived neurotrophic factor, mammalian target of rapamycin activation, and glycogen synthase kinase-3 inhibition. Current efforts aim to extend ketamine's efficacy, uncover neurobiological mechanisms in biologically enriched subgroups, and identify biomarkers for personalized treatment. Other NMDA receptor antagonists show modest antidepressant effects but potentially fewer dissociative or psychotomimetic effects, prompting development of novel glutamatergic antidepressants with greater target specificity and fewer adverse effects.
The Journal of Clinical Psychiatry
May 15, 2014
Mark J. Niciu, David A. Luckenbaugh, Dawn F. Ionescu et al.
167 citations
Higher body mass index and a family history of alcohol use disorder in a first-degree relative were associated with greater improvement in depression symptoms after a single ketamine infusion. Patients with no prior suicide attempts also showed greater improvement, but only at day 7. The analysis combined data from four studies of treatment-resistant inpatients with major depressive disorder or bipolar depression who received a single 0.5 mg/kg ketamine infusion over 40 minutes. The findings suggest that certain clinical characteristics may help predict who benefits most from ketamine's rapid antidepressant effects, though the analysis was post hoc and the models explained only 13% to 36% of the variation in symptom improvement.
The Journal of Clinical Psychiatry
September 8, 2009
Rodrigo Machado‐Vieira, Peixiong Yuan, Nancy E. Brutsché et al.
154 citations
Ketamine produces rapid antidepressant effects in people with treatment-resistant major depressive disorder, but these effects are not linked to changes in brain-derived neurotrophic factor (BDNF) levels. In 23 adults aged 18 to 65, a single intravenous infusion of ketamine (0.5 mg/kg) significantly improved depression scores on the Montgomery-Asberg Depression Rating Scale within 230 minutes. However, BDNF levels measured at the same time points did not change from baseline, and no association appeared between antidepressant response and BDNF. The findings indicate that ketamine's initial antidepressant action operates through mechanisms other than BDNF.
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.
Current Neuropharmacology
March 25, 2016
Brittany A. Jaso, Mark J. Niciu, Nicolas D. Iadarola et al.
97 citations
Current antidepressants for major depressive disorder work through monoaminergic mechanisms and have a delayed onset and limited efficacy. Glutamate, the main excitatory neurotransmitter, is involved in depression's pathophysiology. Since ketamine, an NMDA receptor antagonist, showed rapid antidepressant effects in 2000, other NMDA receptor antagonists have been studied but with more modest effects. Some have advantages like oral administration and fewer side effects. This article reviews clinical evidence for glutamate receptor modulators: non-competitive NMDA antagonists (ketamine, memantine, dextromethorphan, AZD6765), NR2B-subunit antagonists (traxoprodil, MK-0657), glycine-site partial agonists (D-cycloserine, GLYX-13), and metabotropic glutamate receptor modulators (AZD2066, basimglurant). Preclinical targets like AMPA agonists and mGluR2/3 negative allosteric modulators are also discussed.