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Ketamine, major depressive disorder, treatment resistant

Mark J Niciu, Bridget J Shovestul, Brittany A Jaso, Cristan Farmer, David A Luckenbaugh, Nancy E Brutsche, Lawrence T Park, Elizabeth D Ballard, Carlos A Zarate
BACKGROUND: Ketamine induces rapid and robust antidepressant effects, and many patients also describe dissociation, which is associated with antidepressant response. This follow-up study investigated whether antidepressant efficacy is uniquely related to dissociative symptom clusters. METHODS: Treatment-resistant patients with major depressive disorder (MDD) or bipolar disorder (BD) (n = 126) drawn from three studies received a single subanesthetic (0.5 mg/kg) ketamine infusion...
February 17, 2018: Journal of Affective Disorders
Dawn F Ionescu, Julia M Felicione, Aishwarya Gosai, Cristina Cusin, Philip Shin, Benjamin G Shapero, Thilo Deckersbach
Major depressive disorder (MDD) is one of the most prevalent conditions in psychiatry. Patients who do not respond to traditional monoaminergic antidepressant treatments have an especially difficult-to-treat type of MDD termed treatment-resistant depression. Subanesthetic doses of ketamine-a glutamatergic modulator-have shown great promise for rapidly treating patients with the most severe forms of depression. As such, ketamine represents a promising probe for understanding the pathophysiology of depression and treatment response...
February 20, 2018: Harvard Review of Psychiatry
Elizabeth D Ballard, Julia S Yarrington, Cristan A Farmer, Marc S Lener, Bashkim Kadriu, Níall Lally, Deonte Williams, Rodrigo Machado-Vieira, Mark J Niciu, Lawrence Park, Carlos A Zarate
BACKGROUND: Due to the heterogeneity of depressive symptoms-which can include depressed mood, anhedonia, negative cognitive biases, and altered activity levels-researchers often use a combination of depression rating scales to assess symptoms. This study sought to identify unidimensional constructs measured across rating scales for depression and to evaluate these constructs across clinical trials of a rapid-acting antidepressant (ketamine). METHODS: Exploratory factor analysis (EFA) was conducted on baseline ratings from the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Snaith-Hamilton Pleasure Rating Scale (SHAPS)...
February 5, 2018: Journal of Affective Disorders
Chinnakkaruppan Adaikkan, Elham Taha, Iliana Barrera, Orit David, Kobi Rosenblum
BACKGROUND: Ketamine is an N-methyl-D-aspartate receptor antagonist, which on administration produces fast-acting antidepressant responses in patients with major depressive disorder. Yet, the mechanism underlying the antidepressant action of ketamine remains unclear. METHODS: To unravel the mechanism of action of ketamine, we treated wild-type C57BL/6 mice with calcium/calmodulin-dependent protein kinase II (CaMKII) specific inhibitor tatCN21 peptide. We also used eukaryotic elongation factor 2 kinase (eEF2K) (also known as CaMKIII) knockout mice...
December 5, 2017: Biological Psychiatry
Haiying Tang, Daniel Kukral, Yu-Wen Li, Matthew Fronheiser, Harold Malone, Adrienne Pena, Rick Pieschl, Kurex Sidik, Gabriel Tobon, Patrick L Chow, Linda J Bristow, Wendy Hayes, Feng Luo
Major depressive disorder is a leading cause of disability globally. Improvements in the efficacy of antidepressant therapy are needed as a high proportion (>40%) of individuals with major depressive disorder fail to respond adequately to current treatments. The non-selective N-methyl-D-aspartate receptor channel blocker, (±)-ketamine, has been reported to produce a rapid and long-lasting antidepressant response in treatment-resistant major depressive disorder patients, which provides a unique opportunity for investigation of mechanisms that mediate its therapeutic effect...
January 1, 2018: Journal of Psychopharmacology
N Yao, O Skiteva, X Zhang, P Svenningsson, K Chergui
Low doses of ketamine trigger rapid and lasting antidepressant effects after one injection in treatment-resistant patients with major depressive disorder. Modulation of AMPA receptors (AMPARs) in the hippocampus and prefrontal cortex is suggested to mediate the antidepressant action of ketamine and of one of its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). We have examined whether ketamine and (2R,6R)-HNK affect glutamatergic transmission and plasticity in the mesolimbic system, brain regions known to have key roles in reward-motivated behaviors, mood and hedonic drive...
November 21, 2017: Molecular Psychiatry
Katja Weckmann, Michael J Deery, Julie A Howard, Renata Feret, John M Asara, Frederik Dethloff, Michaela D Filiou, Jamie Iannace, Christiana Labermaier, Giuseppina Maccarrone, Christian Webhofer, Larysa Teplytska, Kathryn Lilley, Marianne B Müller, Christoph W Turck
Fewer than 50% of all patients with major depressive disorder (MDD) treated with currently available antidepressants (ADs) show full remission. Moreover, about one third of the patients suffering from MDD does not respond to conventional ADs and develop treatment-resistant depression (TRD). Ketamine, a non-competitive, voltage-dependent N-Methyl-D-aspartate receptor (NMDAR) antagonist, has been shown to have a rapid antidepressant effect, especially in patients suffering from TRD. Hippocampi of ketamine-treated mice were analysed by metabolome and proteome profiling to delineate ketamine treatment-affected molecular pathways and biosignatures...
November 17, 2017: Scientific Reports
Kenji Hashimoto
Depression is often misdiagnosed as major depressive disorder in patients with bipolar disorder. Therapeutic drugs for these two disorders are quite different, but the anesthetic ketamine shows fast-acting antidepressant effects in treatment-resistant patients with these disorders. Here, we discuss biomarkers for both disorders, recent findings regarding ketamine, and predictable biomarkers for ketamine's antidepressant actions.
October 2017: Brain and Nerve, Shinkei Kenkyū No Shinpo
Mark J Niciu, Nicolas D Iadarola, Dipavo Banerjee, David A Luckenbaugh, Minkyung Park, Marc Lener, Lawrence Park, Dawn F Ionescu, Elizabeth D Ballard, Nancy E Brutsche, Nirmala Akula, Francis J McMahon, Rodrigo Machado-Vieira, Allison C Nugent, Carlos A Zarate
BACKGROUND: This study sought to reproduce, in a larger sample, previous findings of a correlation between smaller raw 3-Tesla (3T) hippocampal volumes and improved antidepressant efficacy of ketamine in individuals with major depressive disorder (MDD). A secondary analysis stratified subjects according to functional BDNF rs6265 (val66met) genotype. METHODS: Unmedicated subjects with treatment-resistant MDD ( n=55) underwent baseline structural 3T MRI. Data processing was conducted with FSL/FIRST and Freesurfer software...
December 2017: Journal of Psychopharmacology
Linda J Bristow, Jyoti Gulia, Michael R Weed, Bettadapura N Srikumar, Yu-Wen Li, John D Graef, Pattipati S Naidu, Charulatha Sanmathi, Jayant Aher, Tanmaya Bastia, Mahesh Paschapur, Narasimharaju Kalidindi, Kuchibhotla Vijaya Kumar, Thaddeus Molski, Rick Pieschl, Alda Fernandes, Jeffrey M Brown, Digavalli V Sivarao, Kimberly Newberry, Mark Bookbinder, Joseph Polino, Deborah Keavy, Amy Newton, Eric Shields, Jean Simmermacher, James Kempson, Jianqing Li, Huiping Zhang, Arvind Mathur, Raja Reddy Kallem, Meenakshee Sinha, Manjunath Ramarao, Reeba K Vikramadithyan, Srinivasan Thangathirupathy, Jayakumar Warrier, Imadul Islam, Joanne J Bronson, Richard E Olson, John E Macor, Charlie F Albright, Dalton King, Lorin A Thompson, Lawrence R Marcin, Michael Sinz
( R )-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3 S ,4 S )-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate N -methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4...
December 2017: Journal of Pharmacology and Experimental Therapeutics
Wallace C Duncan, Elizabeth D Ballard, Carlos A Zarate
Ketamine, a drug with rapid antidepressant effects and well-described effects on slow wave sleep (SWS), is a useful intervention for investigating sleep-wake mechanisms involved in novel therapeutics. The drug rapidly (within minutes to hours) reduces depressive symptoms in individuals with major depressive disorder (MDD) or bipolar disorder (BD), including those with treatment-resistant depression. Ketamine treatment elevates extracellular glutamate in the prefrontal cortex. Glutamate, in turn, plays a critical role as a proximal element in a ketamine-initiated molecular cascade that increases synaptic strength and plasticity, which ultimately results in rapidly improved mood...
September 23, 2017: Handbook of Experimental Pharmacology
G H Vázquez, S Camino, L Tondo, Ross J Baldessarini
BACKGROUND: Treatments for depression in bipolar disorder (BD) are far less well developed than for unipolar major depressive disorder. Several innovative and experimental approaches have been emerging recently, including use of the dissociative anesthetic ketamine and other antagonists of central NMDA glutamate receptors, as well as unsaturated fatty acids, anti-inflammatory agents, and possibly probiotic methods. METHODS: We reviewed relevant reports from the past decade...
July 28, 2017: CNS & Neurological Disorders Drug Targets
David Feifel, Benjamin Malcolm, Danielle Boggie, Kelly Lee
BACKGROUND: Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system...
October 15, 2017: Journal of Affective Disorders
B Kadriu, P W Gold, D A Luckenbaugh, M S Lener, E D Ballard, M J Niciu, I D Henter, L T Park, R T De Sousa, P Yuan, R Machado-Vieira, C A Zarate
Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG-RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD...
May 30, 2017: Molecular Psychiatry
Maxim Zavorotnyy, Ina Kluge, Kathrin Ahrens, Thomas Wohltmann, Benjamin Köhnlein, Patricia Dietsche, Udo Dannlowski, Tilo Kircher, Carsten Konrad
Objective of the study was to compare two commonly used anesthetic drugs, S-ketamine and etomidate, regarding their influence on seizure characteristics, safety aspects, and outcome of electroconvulsive therapy (ECT) in major depression. Treatment data of 60 patients who underwent a total number of 13 ECTs (median) because of the severe or treatment-resistant major depressive disorder (DSM-IV) were analyzed. Etomidate, mean dosage (SD) = 0.25 (0.04) mg/kg, was used for anesthesia in 29 participants; 31 patients received S-ketamine, mean dosage (SD) = 0...
December 2017: European Archives of Psychiatry and Clinical Neuroscience
Anna E Martin, Douglas A Schober, Alexander Nikolayev, Vladimir V Tolstikov, Wesley H Anderson, Richard E Higgs, Ming-Shang Kuo, Anastasia Laksmanan, John T Catlow, Xia Li, Christian C Felder, Jeffrey M Witkin
Conventional antidepressants lack efficacy for many patients (treatment-resistant depression or TRD) and generally take weeks to produce full therapeutic response in others. Emerging data has identified certain drugs such as ketamine as rapidly-acting antidepressants for major depressive disorder and TRD. Scopolamine, a drug used to treat motion sickness and nausea, has also been demonstrated to function as a rapidly-acting antidepressant. The mechanisms associated with efficacy in TRD patients and rapid onset of action have been suggested to involve a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling...
March 9, 2017: CNS & Neurological Disorders Drug Targets
Kazuki Nagayasu
Growing evidence indicates that serotonergic neurons play a crucial role in brain function and dysfunction, such as in major depressive disorder. However, the complexity of serotonergic projections severely hampers the elucidation of their precise mechanisms. Here we summarize our recent studies on the effects of ketamine and olanzapine, which have been reported to be effective in treatment-resistant depression, on dorsal raphe nucleus serotonergic neurons, using microdialysis, electrophysiology experiments, and slice cultures...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
M Frere, J Tepper
Major Depressive Disorder (MDD) is a debilitating mental health condition which accounts for a significant portion of worldwide disability. Historically, the suggested pharmacotherapy to treat MDD have been monoaminergic-acting antidepressants, such as SSRIs or SNRIs. These drugs can provide relief, but often take weeks to noticeably improve depressive symptoms and are not always effective, leading to a condition known as Treatment-Resistant Depression (TRD). It is believed that 50% MDD sufferers in Ireland suffer from TRD, and thus the development of improved pharmacotherapies is necessary...
September 9, 2016: Irish Medical Journal
Katerina Papadimitropoulou, Carla Vossen, Andreas Karabis, Christina Donatti, Nicole Kubitz
OBJECTIVE: Major depressive disorder (MDD) affects about 10-15% of the general population in a lifetime. A considerable number of patients fail to achieve full symptom remission despite adequate treatment and are considered treatment resistant (TRD). The current study compared the relative efficacy and tolerability of pharmacological and somatic TRD interventions by means of a Bayesian network meta-analysis. RESEARCH DESIGN AND METHODS: An electronic literature search of MEDLINE, MEDLINE In-Process, EMBASE, PsycInfo, EconLit and Cochrane Library databases for trials published between September 2003 and September 2014 was conducted...
April 2017: Current Medical Research and Opinion
Martha Finnegan, Karen Ryan, Enda Shanahan, Andrew Harkin, Leslie Daly, Declan M McLoughlin
BACKGROUND: Major depressive disorder is a common debilitating illness that is the second leading contributor to the global burden of disease. Unfortunately, about 30 % of patients do not respond to adequate trials of antidepressants and/or psychotherapies. About 45-60 % of such treatment-resistant patients will remit with electroconvulsive therapy (ECT). However, relapse rates are high following ECT-38 % after 6 months. There is a need for better relapse prevention strategies. One possibility is to use ketamine, a competitive glutamate receptor antagonist used for anaesthesia...
2016: Pilot and Feasibility Studies
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