Behavioral Health

Ketamine's Therapeutic Value in Suicidal Patients

A dearth of acute interventions for mental and behavioral health means we discharge many of our most at-risk patients home without first being able to significantly reduce their symptoms. Can ketamine help?

The management of an acute mental health crisis is often a daily occurrence in the practice of emergency medicine, and yet many of us can feel out of our element when confronted with a suicidal patient. We are comfortable running through our ABCs, looking for acute, life-threatening medical pathology. If a patient presents with an acute abdomen, a gunshot wound, or respiratory failure, we can expect our consultants to expedite the patient's care after our evaluation and stabilization.

But when it comes to first-line treatments for suicidality, our options for acute intervention are limited.

The patient often spends hours in the ED awaiting an evaluation by a mental health provider. Some patients may then be referred to inpatient care, whereas others are merely encouraged to connect with an outpatient psychiatrist. If they are prescribed a selective serotonin reuptake inhibitor (SSRI), many will have to wait several weeks before deriving any benefit — and even then, only 40-60% will respond significantly to their first antidepressant trial.1,2 Side effects from SSRIs are nearly universal, with studies showing 90% of patients reporting at least 1 side effect and half of patients reporting a moderate to severe side effect. Amongst those who discontinue their SSRI (up to 72% by day 90 of treatment), 36-62% report doing so because of side effects.3

Thus the unsettling reality is that the dearth of acute interventions means we discharge many of our depressed patients home without first being able to significantly reduce their symptoms. This is particularly worrisome in light of data suggesting that the risk of suicide increases immediately after discharge.4 But it doesn't have to be this way.

An anesthetic that the World Health Organization has listed as an essential medicine since 1985, in part due to its "high level of safety," has been quietly revolutionizing the treatment of depression for the past 15 years. In 2014 Dr. Thomas Insel, former director of NIMH, declared that this drug "might be the most important breakthrough in antidepressant treatment in decades."5

That drug is ketamine.

It turns out that ketamine isn't unique just in its ability to induce anesthesia without significantly impairing the respiratory drive. It also has a robust antidepressant effect, with as many as 70% or more of patients experiencing clinical relief.6 But what makes it so revolutionary, and of particular interest to emergency physicians, is that it works fast — within 4 hours fast for most patients. And effects can persist, with studies demonstrating the benefit of a single infusion often enduring for 7-14 days.7

In the late 1990s, researchers began to realize that the story behind depression is more complicated than simple deficiencies in monoamines. Investigators noticed that the glutamate system also appears to be dysregulated, with hypofunctioning NMDA activity in cortical regions and hyperfunctioning NMDA activity in subcortical regions.7 Relying on one of the most widely used NMDA modulators, ketamine, in 2000 Berman et al. conducted a small, double-blind RCT where they gave an infusion of 0.5 mg/ kg IV over 40 minutes to 7 patients. Scores on a depression scale started to decrease within hours of the infusion and continued to fall over the next 3 days.8

Since then, many studies have been conducted throughout the world with consistent results. Ketamine works for the majority of depressed patients, it works fast, and the effects of a single dose persist long after the drug has been completely metabolized.9 It appears that ketamine causes a release of brain-derived neurotrophic factor, causing synaptogenesis and other significant neuroplastic changes in a number of important brain regions, including the amygdala, hippocampus, dorsal anterior cingulate cortex, prefrontal cortex, and supplementary motor area.10-12 And in 2017 a meta-analysis by Wilkinson et al. helped identify ketamine as belonging to an exclusive club. Alongside lithium, clozapine, cognitive behavioral therapy, and dialectical behavioral therapy, ketamine has been shown to reduce suicidality, independent of its effect of improving depression.13

Research is ongoing, looking for the ideal dosing, route of administration, and frequency of administration. The dosage that is used most commonly in these studies, 0.5 mg/kg, is far below the anesthetic threshold (often 1.0-4.5 mg/kg IV) and recreational amounts (often 0.45-1.45 mg/kg), yet can still induce transient intoxication and feeling of disassociation.7,14 Studies show that giving a bolus is as effective as infusing the dose over an hour.15

In addition to the intoxicating effects, ketamine has been documented to impact other bodily systems, including cardiovascular (elevated BP and heart rate), neurologic (headache, dizziness, unsteadiness), cognitive (memory loss, confusion, poor concentration), and gastrointestinal (nausea and vomiting).16 Despite these effects, researchers have found that when a patient is safely seated during an infusion, occasionally observing the patient and monitoring vitals is sufficient for keeping them safe.15

Many pharmaceutical companies are currently investigating molecules similar to ketamine, hoping to find one that retains ketamine's rapid antidepressant effects but without the inebriation. The FDA very recently granted approval to a groundbreaking Johnson & Johnson nasal spray of esketamine, the S(+) enantiomer of ketamine. But with an estimated cost of $800 per dose, or $4,720-$6,785 per month, and physician unfamiliarity with the drug, it is possible that many of the patients who need it most will not receive prompt access.17 

While drug companies continue searching for the best way to harness the antidepressant effects of ketamine, people continue to experience immense suffering from inadequately treated depression and suicidality. This has led to the creation of ketamine clinics in many large cities across the country, where providers are giving depressed patients off-label infusions of ketamine. While these clinics have improved access to this novel treatment for refractory depression, their high cost places it out of reach for many. And it might not be long before ketamine is approved for the treatment of other disorders, as preliminary data suggests that it improves suffering in those struggling with PTSD, bipolar disorder, social anxiety, chronic pain.18-21

The field of emergency medicine has much to gain by the development of a fast-acting antidepressant. If we were able to provide infusions in the acute setting for depressed and suicidal patients, as has been done in research studies around the world,22-24 we could be more confident that our patients can stay safe upon discharge. Or perhaps we can administer a dose of the newly approved esketamine to our suicidal patients, increasing access to a drug that might otherwise be out of reach for many.

Imagine if, instead of telling our patients that they need to survive incredible distress and pervasive thoughts of death for a month or more before our medications start to work, we could give them a solution that provides immediate relief. What if we had a drug that could serve as a bridge, helping patients stay safe in the short term as they wait for their SSRIs and/ or therapy to start to ameliorate their suffering? And better yet, what if this drug had a proven track record with decades of use and minimal side effects?

We have all of this in ketamine. And no one is better suited to advocate for making it accessible — whether through the newly approved albeit expensive nasal spray or the more traditional, and cheaper, infusion — for patients in the midst of a mental health crisis than emergency physicians, the first providers these patients often encounter following an admission of suicidality or an attempt at taking their life.


References
1. Uher R, Mors O, Rietschel M, et al. Early and delayed onset of response to antidepressants in individual trajectories of change during treatment of major depression: a secondary analysis of data from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. J Clin Psych. 2011.
2. Carvalho AF, Cavalcante JL, Castelo MS, et al. Augmentation strategies for treatment-resistant depression: a literature review. J Clin Pharm Ther. 2007;32(5):415-28.
3. Fortney JC, Pyne JM, Edlund MJ, Stecker T, Mittal D, Robinson DE, Henderson KL. Reasons for antidepressant nonadherence among veterans treated in primary care clinics. J Clin Pscych. 2011;72(6):827-834.
4. Mitchell AM, Garand L, Dean D, Panzak G, Taylor M. Suicide assessment in hospital emergency departments: implications for patient satisfaction and compliance. Topics in Emerg Med. 2005;27(4):302.
5. Insel T. (2014, October 1). Post by former NIMH directory Thomas Insel: Ketamine. Retrieved from http://www.nimh.nih.gov.
6. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psych. 2006;63(8):856-864.
7. Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: From monoamines to glutamate. Exper Clin Pscyhopharmacol. 2015;23(1):1.
8. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biologic Psychol. 2000;47(4):351-354.
9. DrugBank (2019, February 17). Ketamine. Retrieved from https://www.drugbank.ca
10. Zunszain PA, Horowitz MA, et al. Ketamine: synaptogenesis, immunomodulation and glycogen synthase kinase-3 as underlying mechanisms of its antidepressant properties. Mol. Psychiatry. 2013;18(12):1236–1241.
11. Abdallah CG, Adams TG, et al. Ketamine's mechanism of action: a path tovrapid-acting antidepressants. Depress Anxiety. 2016;33(8):689-697.
12. Lener MS, Niciu MJ, et al. Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine. Biol Psychiatry. 2016;
13. Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psych. 2017;175(2):150-158.
14. Erowid (2016, April 13). Ketamine Dosage. Retrieved from https://erowid.org
15. Katalinic N, Lai R, Somogyi A, Mitchell PB, Glue P, Loo CK. Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Australian & New Zealand Journal of Psychiatry, 2013;47(8):710-727.
16. Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. The Lancet Psychiatry. 2018;5(1):65-78.
17. Hamilton J (2019, March 5). FDA Approves Esketamine Nasal Spray For Hard-To-Treat Depression. Retrieved from https://npr.org
18. Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Translational Psychiatry. 2014;4(10), e469.
19. Albott CS, Lim KO, Forbes MK, et al. Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression. J Clin Psych. 2018;79(3).
20. Taylor JH, Landeros-Weisenberger A, Coughlin C, et al. Ketamine for social anxiety disorder: A randomized, placebo-controlled crossover trial. Neuropsychopharmacology. 2018;43(2):325.
21. Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-based review. Anesthesia & Analgesia. 2003;97(6):1730-1739.
22. Kashani P, Yousefian S, Amini A, Heidari K, Younesian S, Hatamabadi HR. The effect of intravenous ketamine in suicidal ideation of emergency department patients. Emergency. 2014;2(1):36.
23. Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharm. 14(8):1127-1131.
24. Burger J, Capobianco M, Lovern R, Boche B, Ross E, Darracq MA, McLay R. A double-blinded, randomized, placebo-controlled sub-dissociative dose ketamine pilot study in the treatment of acute depression and suicidality in a military emergency department setting. Military Medicine. 2016;181(10):1195-1199.

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