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Could Ketamine Be the Answer to Treating Treatment-Resistant Major

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Could Ketamine Be the Answer to Treating Treatment-Resistant Major Open access Review Gen Psych: first published as 10.1136/gpsych-2020-100227 on 18 August 2020. Downloaded from Could ketamine be the answer to treating treatment- resistant major depressive disorder? Abdullah Mohammed Ramadan, Islam Ahmed Mansour To cite: Ramadan AM, ABSTRACT options available in the form of selective Mansour IA. Could ketamine be Major depressive disorder (MDD) is a common, serious, serotonin reuptake inhibitors (SSRI), tricy- the answer to treating treatment- debilitating condition affecting 350 million people clic antidepressants (TCA) and monoamine resistant major depressive worldwide, which remains to be unsatisfactorily treated disorder? General Psychiatry oxidase inhibitors (MAOI), none of them with 53% of patients still complaining of symptoms 2020;33:e100227. doi:10.1136/ were capable of completely relieving the gpsych-2020-100227 after completing their courses with the correct dosage. Ketamine, which was approved by the Food and Drug symptoms of depression and many cases have Received 23 March 2020 Administration in 2019, is a potential treatment option for reported frequent relapses, almost 53%, after Revised 17 June 2020 those recalcitrant cases. The mechanism of ketamine is completing the courses of their medications 2 Accepted 08 July 2020 not fully understood, but as type it is classified as anN - with the appropriate doses with 20% failing methyl-D- asparta te (NMDA) glutamate receptor antagonist, to show improvement on usage of subsequent and can be given intravenously, intranasally and orally. It is lines of therapy.2 4 The current economic used to treat treatment- resistant depression, depression burden of MDD in the USA alone is estimated associated with suicidal ideation, mood and anxiety at $29–$48 billion per year.5 In fact, it carries disorders and depressions associated with either type of a major economic burden in the form of the bipolar disorder. Although ketamine is considered relatively safe, several side effects have been reported with the requirement of numerous emergency rooms, major ones being psychiatric in the form of worsening lacking of responsiveness to the current medi- mood, anxiety and agitation; psychotomimetic in the form cations and major unemployment to many 2 6 of dissociation, perceptual disturbance and abnormal healthcare professionals. sensations; cardiovascular in the form of increased blood Currently, there is no consensus on the pressure and increased heart rate; and neurological in definition of treatment- resistant depression the form of headache and dizziness. Ketamine is still not (TRD), but the current definition is that it is http://gpsych.bmj.com/ approved worldwide for usage in patients with treatment- any form of depression in which the patient resistant MDD, but if it is approved sometime in the is not fully relieved from the major symptoms future with relatively fewer side effects, it is expected to significantly save millions of dollars spent yearly on of depression after taking the appropriate patients with treatment-resistant depression and that courses of at least two antidepressant medica- 2–5 will lift this major burden off the shoulders of healthcare tions at their adequate time duration. The professionals. This study was designed to measure the main limitation in the usage of these agents, effects of ketamine, an NMDA receptor antagonist, on besides the lack of appropriate responsive- on October 2, 2021 by guest. Protected copyright. patients with treatment-resistant MDD and to analyse ness, is the fact that they could take more than the concept that makes it different and relatively safer 2–4 weeks in order for the initial response to than other major antidepressants like selective serotonin be felt by the patients; in addition numerous reuptake inhibitors, monoamine oxidase inhibitors and studies have shown that many patients report TCAs (tricyclic antidepressants). multisystemic, unbearable side effects.7 8 In March 2019, the US Food and Drug © Author(s) (or their employer(s)) 2020. Re- use INTRODUCTION Administration (FDA) approved a new anti- permitted under CC BY-NC. No Major depressive disorder (MDD) is a serious depressant medication under the name of commercial re- use. See rights ketamine, an N- methyl- D- aspartate (NMDA) and permissions. Published by condition that affects the lives of many indi- BMJ. viduals globally. It is estimated that the total type of glutamate receptor antagonist. This Psychiatry, Mansoura University number of cases diagnosed with MDD is 350 review is dedicated to knowing the pharma- 1 2 Faculty of Medicine, Mansoura, million people around the world. And cological details of this medication and how it Egypt eight hundred thousand patients die every is different from other antidepressants in the year due to suicidal ideation caused by MDD. management of TRD.7 8 Correspondence to Dr Abdullah Mohammed MDD poses major burdens to the health- Ketamine is not a perfect drug. Although Ramadan; care systems of different countries around studies in many patients have been shown boodi000@ icloud. com the world.1–3 Despite the different treatment to produce positive results in patients with Ramadan AM, Mansour IA. General Psychiatry 2020;33:e100227. doi:10.1136/gpsych-2020-100227 1 General Psychiatry TRD, they have shown that significant side effects have nausea, vomiting and headache were the reported side Gen Psych: first published as 10.1136/gpsych-2020-100227 on 18 August 2020. Downloaded from caused many cases to cease undergoing drug trials. Espe- effects in most of the studies.9 cially patients with chronic cardiovascular conditions like myocardial infarction, arteriovenous fistulae and chronic hypertension should not be allowed to use ketamine. MECHANISM OF ACTION Currently, there is no full consensus among authors on the exact mechanism/s by which ketamine plays a role in the management of TRD. Basically, ketamine is an USES AND DOSAGE antagonist that blocks the NMDA receptors, but evidence Ketamine is an NMDA receptor antagonist that is used based on numerous studies has proven that the rapid in the management of TRDs, depression associated with antidepressant (RAAD) effect that ketamine establishes is suicidal ideation, mood and anxiety disorders and depres- not based on its NMDA receptor antagonism. While other sions associated with either type of bipolar disorder. Unlike FDA- approved antidepressants have their antidepressant other NMDA antagonists, like memantine that is used in roles derived from their effects on monoamines such as the symptomatic management of Alzheimer’s disease, serotonin, norepinephrine and dopamine, the emer- the mechanism by which ketamine deals with depression gence of ketamine has provided a new perspective that follows a different pathway. It is not fully understood is based on its effects on the glutamate system providing how ketamine treats depression, but it works by different RAAD effects within 4 hours with a long- term effect that mechanisms. Ketamine could be given by three different lasts for 1 week after a single dose.19 9 10 methods: orally, intravenously and nasally. Numerous publications have stated that ketamine induces synaptogenesis at the level of the prefrontal cortex, Intravenously a part of the brain that atrophies in depressed patients.20 The majority of the randomised controlled trials using a Other studies have also shown that ketamine upregulates dose of 0.5 mg/kg over 40 min of intravenous ketamine the activity of a certain type of receptors called glutamate followed by a 20% saline infusion washout have shown alpha- amino-3- hydroxy-5- methyl-4- isoxazolepropionic significant improvement in depression symptoms and acid (AMPA) which plays an important role in increasing suicidal ideation within 1 week as measured using the the levels of the mammalian target of rapamycin Montgomery and Asberg Depression Rating Scale (mTOR) which induces synaptogenesis at the level of the (MADRS).11 12 Response rates for patients using intrave- prefrontal cortex.21 22 Some authors have come to merge nous ketamine were shown to be 50%–70%, which proves the two hypotheses, as shown in figure 1, concluding that to be better than other classes of antidepressants.13 14 the NMDA receptor antagonistic effect of ketamine on Most of the patients have not reported any serious side GABAergic interneurons induces the release of gluta- effects12; however, some patients decided to stop taking mate from the prefrontal cortex which in turn activates the drug after showing major side effects. the AMPA receptors. This activation has been shown to http://gpsych.bmj.com/ urge the release of brain-derived neurotrophic factor and Intranasal The US FDA has recently approved the usage of intra- nasal esketamine along with an oral antidepressant. The doses used in most of the studies were an initial dose of 28 mg/kg and a maintenance dose of 56 or 84 mg/kg. Most cases have statistically shown significant improvements on October 2, 2021 by guest. Protected copyright. over 40 min according to the MADRS score. Some major side effects were shown in some patients mainly because of the high level of bioavailability of esketamine as it has no first- pass metabolism.15 Those side effects included dissociation, fatigue, poor memory, severe headaches, nausea, elevated heart rate and blood pressure. Oral Figure 1 Ketamine works by two currently merged Oral ketamine undergoes a high level of the first- pass mechanisms: N- methyl- D- aspartate (NMDA) receptor and metabolism which makes its bioavailability less than 20%. alpha- amino-3- hydroxy-5- methyl-4- isoxazolepropionic acid (AMPA) receptor mechanisms. The NMDA receptor A small open-label study of oral ketamine with a dose antagonistic effect of ketamine on GABAergic interneurons of 0.5 mg/kg in hospice patients for 28 days has shown induces the release of glutamate from the prefrontal cortex a significant improvement in the MADRS depression which in turn activates the AMPA receptors. AMPAR, AMPA 16–18 scale. The time to response was 1–2 weeks; however, receptor; BDNF, brain- derived neurotrophic factor; GABA, some patients have decided to withdraw from the trial due gamma-aminobutyric acid; GLT-1, glutamate transporter 1; to lack of response.
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