Review Of Ketamine Research Articles

A New Solution to an Age-old Problem: A Review of Ketamine and Esketamine for Treatment-resistant Depression in Late Life

A New Solution to an Age-old Problem: A Review of Ketamine and Esketamine for Treatment-resistant Depression in Late Life

Infusing hope into the treatment of suicidality: A review of ketamine's effects on suicidality.

Given recent increases in rates of suicide and lack of rapid treatments for suicidality, ketamine has been identified as a potential fast-acting anti-suicidal treatment. Our review seeks to describe the effects of ketamine on suicidality, given the growing literature on the use of ketamine in reducing suicidality. We examine open-label studies and randomized controlled trials evaluating treatment of suicidality with ketamine. Furthermore, our manuscript identifies potential mechanisms of ketamine's effects on suicidality. Based on existing RCTs, ketamine appears to have rapid anti-suicidal effects, with most literature studying such effects in timeframes less than one week. Although still in the early stages of research, mechanisms of ketamine include modulation of molecular, inflammatory, neural, cognitive, and behavioral processes. Thus, ketamine appears to be a promising treatment for suicidality, but requires larger scale and more robust RCTs to confirm the potential use of this agent in clinical settings.

KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID-ACTING ANTIDEPRESSANTS.

Major depressive disorder (MDD) is a common and debilitating psychiatric disorder. Traditional antidepressants are of limited efficacy and take weeks to months to yield full therapeutic effects. Thus, there is a clear need for effective rapid-acting antidepressant medications. The N-methyl-d-aspartate receptor (NMDA-R) antagonist, ketamine, has received a great deal of attention over the last 20 years due to the discovery that a single subanesthetic dose leads to a rapid antidepressant effect in individuals with treatment-resistant depression. Animal and human research suggest that ketamine's antidepressant effects are mediated by a glutamate surge that leads to a cascade of events that result in synaptogenesis and reversal of the negative effects of chronic stress and depression, particularly within the prefrontal cortex (PFC). Preclinical and clinical data have provided compelling insights into the mechanisms underlying the rapid-acting antidepressant effects of ketamine. This review discusses stress-related neurobiology of depression and the safety, tolerability, and efficacy of ketamine for MDD, along with a review of ketamine's mechanism of action and prospective predictors of treatment response. Research limitations and future clinical prospects are also discussed.

Reversal of Non-Suppression of Cortisol Levels in a Patient With Refractory Depression Receiving Ketamine

Back to table of contents Previous article Next article Communications and UpdatesFull AccessReversal of Non-Suppression of Cortisol Levels in a Patient With Refractory Depression Receiving KetamineRobert Ostroff, M.D. Jay S. Kothari, M.D.Robert OstroffSearch for more papers by this author, M.D. Jay S. KothariSearch for more papers by this author, M.D.Published Online:1 Jan 2015https://doi.org/10.1176/appi.ajp.2014.14060776AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Research has shown that the hypothalamic-pituitary-adrenal (HPA) axis is involved in the mediation of stress and depression (1). The dexamethasone suppression test (DST) consists of the administration of 1 mg of dexamethasone at 11:00 p.m. and measurement of cortisol at 8:00 a.m. and 4:00 p.m. the following day. Sixty percent of depressed patients do not show the anticipated suppression of cortisol. A positive dexamethasone suppression test is a cortisol level >5 mcg/dl at 8:00 a.m. or 4:00 p.m. (2).Ketamine, administered intravenously, has been found to provide immediate but short-term relief of the depressed state (3–5). We decided to test the hypothesis that reversal of depression would reverse nonsuppression of cortisol levels in a consenting male patient with refractory depression.“Mr. J,” a 46-year-old man with treatment-resistant depression, was hospitalized following a serious suicide attempt. He had failed trials of selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, lithium, lamotrigine, riluzole, and ECT. In preparation for a trial of tranylcypromine, we discontinued the patient’s current medications and initiated intravenous ketamine infusions at 0.5 mg/kg over the course of 40 minutes each. Prior to the patient’s first ketamine infusion, his DST showed nonsuppression, with an 8:00 a.m. cortisol level of 1.7 mcg/ml and a 4:00 p.m. cortisol level of 7.4mcg/ml. After three alternate-day infusions of ketamine, his mood improved dramatically, with a 50% reduction in his Hamilton Depression Rating Scale score. Repeat DST showed suppression with 8:00 a.m. and 4:00 p.m. cortisol levels of 1.1 and 1.0, respectively (normalized). One week after discontinuation of ketamine, the patient’s symptoms returned. Prior to starting the monoamine oxidase inhibitor, and upon re-emergence of symptoms, his cortisol levels were once again nonsuppressed, with levels of 7.7 mcg/ml and 14.5 mcg/ml, respectively.HPA axis dysregulation occurs frequently with depression and with states of stress. To our knowledge, this is the first report demonstrating the use of DST during a ketamine infusion trial to track the changes in the regulation of this axis. The rapid changes in DST from nonsuppression to suppression to nonsuppression mirror the changes in the patient’s state of depressive symptoms. The role of ketamine in the HPA axis in depressed patients needs to be better elucidated and may help us understand the pathophysiology of the depressed state.From the Department of Psychiatry, Yale University, New Haven, Conn.The authors report no financial relationships with commercial interests.References1 Gragnoli C: Hypothesis of the neuroendocrine cortisol pathway gene role in the comorbidity of depression, type 2 diabetes, and metabolic syndrome. Appl Clin Genet 2014; 7:43–53Crossref, Medline, Google Scholar2 Nuller IuL, Ostroumova MN: [Disruption of the homeostatic regulation of adrenal function in endogenous depression]. Zh Nevropatol Psikhiatr Im S S Korsakova 1978; 78:381–385 [Russian]Medline, Google Scholar3 Naughton M, Clarke G, O’Leary OF, et al.: A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord 2014; 156:24–35Crossref, Medline, Google Scholar4 Krystal JH, Sanacora G, Duman RS: Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 2013; 73:1133–1141Crossref, Medline, Google Scholar5 Salvadore G, Singh JB: Ketamine as a fast acting antidepressant: current knowledge and open questions. CNS Neurosci Ther 2013; 19:428–436Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByStress, mental disorder and ketamine as a novel, rapid acting treatmentEuropean Neuropsychopharmacology, Vol. 65Effects of stress on endophenotypes of suicide across species: A role for ketamine in risk mitigationNeurobiology of Stress, Vol. 18 Volume 172Issue 1 January 01, 2015Pages 95-96 Metrics PDF download History Accepted 1 September 2014 Published online 1 January 2015 Published in print 1 January 2015