09-18-17 What is the Role of ketamine in Major Depressive Disorder?

                            Toxicology Question of the Week

                                                                September 18, 2017

A full page ad in the Sunday New York Times promoting IV ketamine for the treatment of depression made me ponder the mechanism of action and actual clinical practice.  So when Jose Vigo (AKA “Beto”), a Fellow in Psychosomatic Medicine, rotated with us, I asked him to educate all of us about this relatively new modality.  See what you think…

ds

What is the Role of ketamine in Major Depressive Disorder?

            Depression is a major public health problem associated with functional disability and mortality. In the United States in 2010, the estimated annual economic consequences of unipolar major depression exceeded 200 billion dollars. Nearly a third of patients don't find relief from antidepressants and other traditional treatments.

            Clinical trials indicate that ketamine improves mood disorders although mechanism of action is unknown. Ketamine is as a dissociative anesthetic and a noncompetitive NMDA receptor antagonist. Ketamine also potentiates glutamate at AMPA receptors (AMPAR) and  inhibit  muscarinic acetylcholine receptors. NMDARs and AMPARs are glutamate receptors found throughout the central nervous system (CNS).  They play a major role in the process by which neurotransmitters are released and activate the receptors of another neuron (neural signaling at excitatory synapses).

            Antidepressants increase the amount of neurotransmitters (serotonin, dopamine and norepinephrine) in the synapse and thereby increase the signaling between neurons. Animal studies indicate ketamine impacts synaptic plasticity (ability of transmitting a signal between neurons to strengthen or weaken over time) and neurotrophic signaling (neuronal signaling mediated by neurotrophins, which promote neural survival and regulate neuronal development and function).

            Among patients with major depression, connectivity between neurons is abnormal, specifically in brain regions that process emotions. Ketamine antagonizes NMDAR which improves communication between neurons, and promotes survival in brain areas involved in processing emotions. If we think of it in terms of a computer, ketamine would be equivalent to a hardware fix whereas traditional antidepressants would be a software fix.

Is treatment with ketamine clinically relevant?

            Since the early 2000s there have been at least 12 well-designed randomized controlled clinical trials (RCT) demonstrating that ketamine improves mood in patients with a depressive episode of bipolar disorder or major depressive disorder (MDD). Ketamine was used as monotherapy (four studies), augmentation strategy of antidepressant medications (three studies) and augmentation strategy of electroconvulsive therapy (five studies). As monotherapy or used to augment the effect of antidepressants, a single dose of intravenous ketamine (0.5 mg/kg) was administered. Conversely, to augment ECT (electroconvulsive therapy) dose ranged from 0.4mg/kg up to 2 mg/kg intravenously. The protocols were inconsistent with regard to dose. 

            While the results are promising, the current recommendations are based on small RCTs with the largest study having a sample size of 72 and the smallest 9 subjects. Intravenous infusion was the method of administration in all but one of the studies, which utilized intranasal administration. Response was defined as a 50 % or greater decrease from baseline whereas remission was defined as less than 10% of the potential maximum depression score in the applied questionnaires.

            Results demonstrated that a single intravenous infusion of ketamine, excluding its use in conjunction with ECT, consistently produced a rapid antidepressant response peaking within one day of administration. A systematic review reported that response rates were significantly higher in the ketamine group compared with placebo (52.6% vs. 7.0% response rate). Treatment response declined steadily but remained statistically significant as long as 2 weeks following ketamine infusion. Overall, if results are stratified of the twelve RCTs , the likelihood of improved mood in the ketamine group at day 7 was almost five-fold higher for major depressive disorder (p = 0.001) but not significant for bipolar disorder.

            The antidepressant effects of ketamine infusion appear to be both rapid and robust, albeit transient. Transient dissociative effects also occurred among those receiving ketamine. Despite ketamine’s long-recognized sympathomimetic properties, the hemodynamic effects of ketamine were systematically reported in only two trials, with those reporting mean systolic blood pressure increases of 7.6 mm Hg and 19.0 mm Hg respectively, forty minutes after infusion. Blood pressure measures returned to baseline within 4 hours of infusion. Blood pressure changes warranting discontinuation of ketamine infusion were observed in only one of the studies.

            Despite the lack of clear established indications for the use of ketamine in the treatment of psychiatric disorders by the FDA (Food and Drug Administration), the American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatment recommends consideration the use of ketamine in patients with major depressive episodes without psychotic features who have not responded to traditional treatments. In addition to diagnostic considerations, medical, psychological, or social factors may alter the risk to benefit ratio of the treatment and affect the patient’s capacity to provide informed consent. The recommended components of pre-procedural evaluation for appropriateness of ketamine hydrochloride treatment are discussed in the referenced article (14). Finally, given the lack of FDA recommendations, insurance companies do not cover this treatment for depression, which prevents major medical centers and academic institutions from implementing it systematically (including Vanderbilt University Medical Center).

This Question was prepared by: Jose A Arriola Vigo, MD. Psychosomatic Medicine Fellow at VUMC

References:

  1. Berman RM, Cappiello A, Anand A, et al: Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47:351–354
  2. Lapidus KA, Levitch CF, Perez AM, et al: A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014; 76:970–976. Available at doi: 10.1016/j.biopsych.2014.03.026
  3. Murrough JW, Iosifescu DV, Chang LC, et al: Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170:1134–1142
  4. Zarate CA Jr, Singh JB, Carlson PJ, et al: A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63:856–864
  5. Diazgranados N, Ibrahim L, Brutsche NE, et al: A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010; 67:793–802
  6. Sos P, Klirova M, Novak T, et al: Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuroendocrinol Lett 2013; 34:287–293
  7. Zarate CA Jr, Brutsche NE, Ibrahim L, et al: Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 2012; 71:939–946
  8. Abdallah CG, Fasula M, Kelmendi B, et al: Rapid antidepressant effect of ketamine in the electroconvulsive therapy setting. J ECT 2012; 28:157–161
  9. Loo CK, Katalinic N, Garfield JBB, et al: Neuropsychological and mood effects of ketamine in electroconvulsive therapy: a randomised controlled trial. J Affect Disord 2012; 142:233–240
  10. Järventausta K, Chrapek W, Kampman O, et al: Effects of S-ketamine as an anesthetic adjuvant to propofol on treatment response to electroconvulsive therapy in treatment-resistant depression: a randomized pilot study. J ECT 2013; 29:158–161
  11. Wang X, Chen Y, Zhou X, et al: Effects of propofol and ketamine as combined anesthesia for electroconvulsive therapy in patients with depressive disorder. J ECT 2012; 28:128–132
  12. Yoosefi A, Sepehri AS, Kargar M, et al: Comparing effects of ketamine and thiopental administration during electroconvulsive therapy in patients with major depressive disorder: a randomized, double-blind study. J ECT 2014; 30:15–21
  13. Newport J, Carpenter L, McDonald W, et al: Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry 2015; 172:10: 950-66.
  14. Sanacora G, Frye MA, McDonald W, et al: A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. April 2017; 74-4: 399-405
  15. Li N, et al. mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science. 2010;329:959–964.
  16. Covington HE, 3rd, et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci. 2010;30:16082–16090.
  17. Murrough J. Ketamine as a Novel Antidepressant: From Synapse to Behavior. Clin Pharmacol Ther. 2012 Feb; 91(2): 303–309. doi: 10.1038/clpt.2011.244
  18. Li N, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011; 69:754–761. 
  19. Li N, et al. mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Science. 2010; 329:959–964.
  20. Singh JB, Fedgchin M, Daly EJ, et al. Adouble-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine inpatients with treatment-resistant depression. Am JPsychiatry. 2016;173(8):816-826.

I am interested in any questions you would like answered in the Question of the Week.  Please email me with any suggestion at donna.seger@vanderbilt.edu

Donna Seger, MD

Medical Director

Tennessee Poison Center

www.tnpoisoncenter.org

Poison Help Hotline: 1-800-222-1222

The Question of the Week is available on our website: www.tnpoisoncenter.org