Painting Ketamine in a Bad Light
In a groundbreaking study, low-dose infusions of ketamine were found to produce a rapid antidepressant response.
A recent Associated Press article suggests that ketamine is not helping those with depression.1 Indeed, the article suggests that ketamine clinics are taking advantage of desperate people with depression using an unproven treatment. In many ways, I disagree with the author of this article. However, in one fundamental way, I agree.
Ketamine has proven extremely helpful for our patients. In my practice, we have seen an 85% response rate based on multiple well-established depression scales.2 But the way we administer ketamine is quite different from the way it is administered in the approximately 150 ketamine clinics scattered across the United States. Most ketamine clinics follow a protocol of administering intravenous ketamine 3 times per week for 2 weeks. Everybody in these clinics gets 6 infusions in 2 weeks at a cost of between $2000 and $3000; however, many of these patients do not feel significantly better after 2 weeks of treatment. Some may feel better for a week or two, but they then slip back into depression. So, all of that effort was a waste of time and money.
Understanding how ketamine works is essential to appreciating why this approach often fails. Ketamine works by 2 major pathways.2 The first is the glycogen synthase kinase-3 (GSK-3) pathway, which results in the rapid antidepressant and antisuicidal benefit of ketamine. However, the second pathway is actually much more important. Ketamine activates the production of brain-derived neurotrophic factor (BDNF), which is the brain's own repair inducer. Not only does ketamine increase BDNF, but it also increases the number of receptors to which BDNF binds. As a result, over time, there is more repair factor and more receptors available to be activated by the repair factor. The outcome is that over a period of weeks, neuroplasticity and repair occur in the brain. This leads to reduction of depression, because depression is the result of the breakdown in circuits and damage to the brain.
A Novel Antidepressant?
The groundbreaking study by Berman and colleagues showed that low-dose infusions of ketamine produced a rapid antidepressant response.3 Additional single-infusion studies of ketamine confirmed this initial finding that ketamine at 0.5 mg/kg infused over a 30- to 40-minute period induces a rapid reduction in depressive symptoms and suicidal ideation in approximately 60% to 75% of patients.3-5 This stood in marked contrast to the decades of disappointing performance of oral antidepressants, which require weeks to work and rarely achieve better than a 40% response rate.6,7
Although the initial response to ketamine was exciting, it also proved to be short lived in most cases. Symptom relief typically lasted only 4 to 10 days. Multiple infusions were explored, but how often should these infusions be given? For the first study of multiple infusions, the decision was made to give infusions 3 times per week.8 This protocol was not based on an understanding of the unique pharmacology of ketamine but merely because this was the treatment protocol for electroconvulsive therapy (ECT; PR Shiroma, personal communication). As a result of an almost random decision, the “established” protocol for ketamine infusions became 3 times per week; however, is this frequency supported by the mechanisms of action of ketamine?
Possible Mechanisms of Depression
To better understand the mechanisms of ketamine, it is helpful to understand the mechanisms of depression. Depression is associated with loss of neurons, reduced synapse numbers, and dearborization of dendrites in the hippocampus and frontal cortices.9-12 In essence, depression is a reversible neurodegenerative process. Currently available antidepressants can potentially increase neural progenitor cells in the hippocampus of rodent models12 and humans13 as well as upregulate BDNF.14 Methods of preventing neurogenesis, such as focal irradiation15 or focal knockdown of BDNF expression, can prevent the behavioral response to monoaminergic antidepressants. Furthermore, dendritic arbors are stripped of branches in animal models of depression9,10 and dendritic spine density decreases markedly.10,16 These structural rearrangements can be partially reversed with monoaminergic antidepressants.11,17 Similar processes likely occur in humans, as the size of the hippocampus is reduced in patients with depression18 based on magnetic resonance imaging. A few studies indicate that hippocampal volume enlarges briefly following ECT19 and possibly following transcranial magnetic stimulation treatment for depression.20 Postmortem studies of patients with depression have revealed decreased BDNF expression in the hippocampus21,22 and loss of neurons. Knockdown of BDNF levels selectively in the hippocampus causes depressive behaviors in mice.23 Rodent models of stress-induced depression show decreased BDNF expression in the hippocampus.24
Possible Mechanisms of Action of Ketamine
The mechanisms underlying the antidepressant effects of ketamine are not simply the result of glutamate receptor inhibition. Rather, ketamine binding to an N-methyl-D-aspartate receptor, if coupled with a mature α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, activates a second messenger system, known as eukaryotic elongation factor 2 (eEF2). The eEF2 then activates BDNF protein synthesis, particularly in neuronal dendrites.24-26 The concomitant depolarization of AMPA receptors leads to release of BDNF, which can then bind to postsynaptic receptors specific for BDNF, called trkB receptors.24,27 The trkB receptors initiate numerous pathways, including early response genes and a DNA signal that leads to increased BDNF translation.12,27 Moreover, BDNF has the ability to regulate the mammalian target of rapamycin (mTOR) and, thus, creates a positive feedback loop leading to further increase in BDNF production.28 Rodent models of depression with decreased BDNF expression in the hippocampus show reversal of depressive behavior and restoration of normal BDNF levels with ketamine treatment,24 overexpression of trkB,29 or local microinfusion of BDNF.30,31
Ketamine also appears to alter GSK-3, which is believed to function abnormally in mood disorders.32 Increased phosphorylation of GSK-3 induced by ketamine is a possible mechanism for its rapid antidepressant effect. For example, a knock-in mouse model in which GSK-3 cannot be phosphorylated lacks an antidepressant response to ketamine.33 GSK-3 is thought to induce mTOR activity, which could lead to increased BDNF levels.12 The well-known antidepressant and mood stabilizer, lithium, which also inhibits GSK-3, potentiates the effects of ketamine on GSK-3 and lithium pretreatment has therefore been proposed as a method of prolonging the antidepressant benefits of ketamine.27,32
The inhibition of ketamine's antidepressant effects has been studied extensively. Blocking the AMPA receptor appears to prevent the effects of ketamine in animal models of depression.32 Blockade of mTOR with rapamycin pretreatment also prevents the antidepressant effects of ketamine in animal models.34 The Associated Press article mentions a small study conducted at Stanford University that suggests that ketamine works by means of opiate receptors.35 The researchers gave patients ketamine infusions at 0.5 mg/kg and observed a decrease in depression scale scores 24 hours later. They then pretreated some patients with naltrexone, an opioid antagonist. Although patients felt woozy during the infusion, they derived no immediate antidepressant benefit. The researchers mistakenly assumed that this indicated ketamine works directly through opiate receptors. There is only one problem: naltrexone also affects AMPA receptors. Ketamine is an AMPA-receptor antagonist. Injecting AMPA-receptor antagonists into the spinal cord increases the response to noxious stimuli in a rodent model; however, this increased response is blocked by the administration of naltrexone.36 Naltrexone administration by itself has no effect on the response to noxious stimuli. Naltrexone and opioid receptors modulate glutamate receptors, including those influenced by ketamine.37 An earlier clinical study of the interplay between naltrexone and ketamine found a considerably different result from that of the Stanford study. Patients with alcohol dependence were given ketamine at low and high doses. The treatment was then repeated, with naltrexone being administered first. Those patients receiving the higher dose of ketamine (0.4 mg/kg) showed no effects from the naltrexone at doses comparable to those used in the Stanford study.38
Notably, trkB inhibition does not block the immediate benefits of ketamine, but it does prevent the enduring effects.24 Similarly, a tyrosine kinase inhibitor that prevents phosphorylation and activation of the trkB receptor also blocks the sustained benefits of ketamine but not its immediate effects. Furthermore, silencing the ventral hippocampus with lidocaine prior to ketamine infusion blocks the long-lasting benefits of ketamine but has no effect on the immediate benefits. These studies have been extensively reviewed elsewhere.25,27,32
Taken together, these data demonstrate that ketamine has both immediate and delayed effects. The immediate effects (via AMPA-receptor activation and the GSK-3 pathway) are the focus of most ketamine clinics. The standard protocol of 3 infusions per week over 2 weeks is wedded to this mechanism but ignores the powerful, long-lasting potential benefit of ketamine. The delayed effects of ketamine likely include activation of eEF2 leading to BDNF translation, enhanced synaptic connectivity, neurogenesis, dendritic arborization, and immunomodulation. The delayed effects potentially underlie persistent neuroplasticity and persistent antidepressant effects.2 These mechanisms may also underlie the neuroregenerative properties of near-infrared light, which also activates BDNF and has immunomodulatory effects.39 Infrared light has recently been shown to have potent antidepressant effects.40
As it takes weeks for this neuroplasticity to develop fully, it should not be surprising that people do not feel better at the end of 2 weeks of ketamine treatment. Moreover, if it takes weeks for BDNF to work, why should a person get 3 infusions in 1 week? That makes no sense. On average, at Neuro-Luminance Brain Health Centers, our patients receive 4.3 ketamine infusions total over their entire treatment course of 5 to 7 weeks.2 Neuro-Luminance's protocols save time, medication exposure, and money, and they yield a superior outcome. Indeed, if a patient is getting infusions 3 times per week at a typical ketamine clinic, they will quickly spend more time and more money in 2 weeks than most patients spend in their entire lifetime at Neuro-Luminance Brain Health Centers Ketamine Infusion Center. We have been operating our ketamine infusion clinic for more than 6 years and have treated in excess of 600 patients. Ketamine is safe, if safely administered. We have seen no evidence of addiction, and only 5% of our patients require more than 7 infusions using our enlightened approach to ketamine.
One additional point from the Associated Press article deserves mention. The author pointedly states that ketamine is not approved by the US Food and Drug Administration (FDA) for the treatment of depression. What most Americans do not know is that FDA approval simply means that a company has government permission to advertise the drug for a specific disease. For example, aspirin is used to treat headaches, prevent strokes, prevent heart attacks, relieve pain, treat arthritis, and reduce fever; however, it is only approved by the FDA for fever and pain relief. So, utilizing ketamine for depression is no different from using aspirin to prevent strokes and heart attacks.
Ultimately, the economic impact of ketamine treatment is significant – not just for the individual but for pharmaceutical companies, as well. For the individual, he or she needs to choose a ketamine clinic that provides ketamine in a smart way – one based on the neurotrophin mechanism of BDNF. By doing so, a patient can spend less in their entire treatment lifespan than many currently spend in the first 2 weeks of treatment. For pharmaceutical companies, there are billions of dollars to be made from the first ketamine analog that doesn't require intravenous administration. Not surprisingly, physicians who put ketamine down and suggest that ketamine clinics are dangerous are often stockholders, consultants, or owners of companies developing oral ketamine analogs.7,41 For example, the authors of the American Psychiatric Association position paper,42 with one exception, are owners, consultants, or stockholders of companies working to corner the ketamine analog market.
Although the preschool teacher mentioned in the Associated Press article had spent $2000 on ketamine infusions so far, it shouldn't come as a surprise if the price of an oral ketamine analog is more than $3000 per month. One simply has to look at Solvadi and other medications that treat hepatitis C; these cost more than $4000 per month. Abilify cost $1035 per month in 2017 after being on the market for 15 years. In fact, until it went generic, Abilify was netting the pharmaceutical company, Otsuka, more than $7 billion per year. Generics are still egregiously expensive, ranging from $627 at Target to $944 at Walgreens for a one-month supply, according to GoodRx.com. With this potential economic windfall, it is not surprising that physicians are motivated to paint ketamine clinics in a bad light. If ketamine is dangerous, then more people will flock to the ketamine analogs, even if they are less efficacious (although this is yet to be determined). I am also concerned that ketamine clinics using the standard protocol are overadministering ketamine. In my extensive experience, the drug does not work any faster when administered with multiple infusions in a week vs a single infusion per week, nor do I see other clinics yielding better response rates than our 80% to 85%. Therefore, caution and education are important as assumptions about the mechanism of ketamine do little to help the situation.
Last, conflicts of interest abound among the vocal leaders of the psychiatric community. Obviously, I have mine. I run a ketamine clinic using a once-per-week (or less) infusion protocol, and I have seen ketamine transform people's lives in a way I have not seen with any other modalities. These patients come to me with a sense of hopelessness. Many have failed ECT or transcranial magnetic stimulation. However, within weeks I see their lives change for the better and most of my patients, upon follow-up, retain these benefits for years afterward. Perhaps I am just lucky…or perhaps approaching ketamine as a neuroregenerative agent rather than a quick fix makes a fundamental difference.
Theodore A. Henderson, MD, PhD, is the founder of Neuro-Luminance Brain Health Centers, Inc. and director of The Synaptic Space.
- Tanner L. Trippy depression treatment? Hopes and hype for ketamine. Associated Press. November 1, 2018. Accessed December 10, 2018.
- Henderson TA. Practical application of the neuroregenerative properties of ketamine: real world treatment experience. Neural Regen Res. 2016;11(2):195-200.
- Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.
- 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(8):856-864.
- Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66(5):522-526.
- Connolly KR, Thase ME. If at first you don't succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs. 2011;71(1):43-64.
- Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB; for the APA Council of Research Task Force on Novel Biomarkers and Treatments. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172(10):950-966.
- Shiroma PR, Johns B, Kuskowski M, et al. Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. J Affect Disord. 2014;155:123-129.
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- Liu RJ, Aghajanian GK. Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc Natl Acad Sci U S A. 2008;105(1):359-364.
- Morais M, Santos PA, Mateus-Pinheiro A, et al. The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition. J Psychopharmacol. 2014;28(12):1178-1183.
- Duman RS. Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues Clin Neurosci. 2014;16(1):11-27.
- Boldrini M, Underwood MD, Hen R, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology. 2009;34(11):2376-2389.
- Engel D, Zomkowski AD, Lieberknecht V, Rodrigues AL, Gabilan NH. Chronic administration of duloxetine and mirtazapine downregulates proapoptotic proteins and upregulates neurotrophin gene expression in the hippocampus and cerebral cortex of mice. J Psychiatr Res. 2013;47(6):802-808.
- Surget A, Saxe M, Leman S, et al. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol Psychiatry. 2008;64(4):293-301.
- Duman CH, Duman RS. Spine synapse remodeling in the pathophysiology and treatment of depression. Neurosci Lett. 2015;601:20-29.
- McAvoy K, Russo C, Kim S, Rankin G, Sahay A. Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age. Hippocampus. 2015;25(11):1429-1446.
- Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93(9):3908-3913.
- Nordanskog P, Larsson MR, Larsson EM, Johanson A. Hippocampal volume in relation to clinical and cognitive outcome after electroconvulsive therapy in depression. Acta Psychiatr Scand. 2014;129(4):303-311.
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- Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN. Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry. 2003;60(8):804-815.
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- Björkholm C, Monteggia LM. BDNF - a key transducer of antidepressant effects. Neuropharmacology. 2016;102:72-79.
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- Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci. 2002;22(8):3251-3261.
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