November/December 2019

Medication Monitor: Ketamine — Hope for Patients With Treatment-Resistant Depression
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 12 No. 6 P. 5

Major depressive disorder (MDD) affects more than 300 million people of all ages globally and is the leading cause of disability worldwide.1 In the United States alone, 17.3 million adults—7.1% of the adult population—experience at least one major depressive episode in a given year.2 For many patients, antidepressants can help relieve symptoms of depression. About one-third of depression sufferers fail to respond to treatment, and those who haven’t adequately responded to at least two different antidepressant treatments for their current depressive episode are considered to have treatment-resistant depression (TRD). Many patients suffering with TRD spend years trying different antidepressant agents, all while continuing to battle symptoms of depression such as persistent feelings of sadness, sleep disturbances, low energy, and thoughts of death or suicide.3  

Self-injurious behaviors (SIBs), including nonsuicidal self-harm and suicidal behavior, affect millions of patients and are commonly associated with MDD, schizophrenia, personality disorders, autism, bipolar disorder, and substance use disorders. There are few pharmacologic treatments for suicidality and self-injurious behavior and none that treat these conditions emergently. In addition to ketamine’s ability to rapidly reverse symptoms of depression, it also appears to help subdue thoughts of suicidal ideation and SIBs.

Today new hope for patients with TRD may come from ketamine, an anesthetic and popular party drug.4 Unlike traditional antidepressants, which take several weeks to work, ketamine has been shown to exhibit antidepressant benefits within hours of an IV infusion.5 As a result of a number of studies demonstrating ketamine’s rapid and robust antidepressant properties, some leaders in mental health have labeled the drug as “arguably the most important discovery (in depression research) in half a century.”6

Ketamine is an injectable dissociative anesthetic first approved and marketed in the United States in the 1970s for use in humans (marketed as Ketalar) and in veterinary medicine.7 It’s been described as a unique drug because its hypnotic, analgesic, and amnesic effects aren’t seen together in any other drug used in clinical practice.8

Ketamine has been used to provide pain relief and short-term memory loss during medical procedures. In surgery, it’s used as an induction and maintenance agent for sedation and to provide general anesthesia. Other uses have included pain control in persons receiving treatment for radiation and burns, in children who cannot use other anesthetics due to allergies, and in those who have sustained battlefield injuries. It was the most widely used battlefield anesthetic during the Vietnam War.7-9

The World Health Organization includes ketamine on its list of minimum medicine needs for a basic health care system, noting it to be a safe anesthetic that doesn’t depress respiration or circulation and that can be used without oxygen, ventilators, electricity supply, and other support systems needed with the use of most anesthetics. For these reasons, ketamine is the only anesthetic suitable for medical and veterinary use in the developing world. Furthermore, it has a particular role in areas of natural disasters and conflict zones where infrastructure is limited.9,10

Illicit Use and Abuse Potential
The Drug Enforcement Administration (DEA) made ketamine a Schedule III controlled substance in 1999. Most of the illicit sourcing of ketamine occurs from diversion from practitioners’ offices, with the primary source being veterinary clinics. Available as a liquid injectable pharmaceutical product, ketamine is injected, or, more commonly, evaporated, with the resultant powder being inhaled (snorted). The DEA notes that clandestine manufacture of ketamine hasn’t been encountered, as, unlike PCP, its synthesis is difficult.7,10

Ketamine, which has a number of street names, including Special K, “K,” and Cat Valium, has been used illicitly during the past 40 years to deliberately induce an altered state of mind. It’s been widely used in clubs and “rave” dance venues and has been implicated as a “date rape” drug. Ketamine and other dissociative drugs such as PCP and dextromethorphan in high doses can distort the way a user perceives time, motion, colors, sounds, and self.7,10 These effects can disrupt a person’s ability to think and communicate rationally or to recognize reality, sometimes resulting in bizarre or dangerous behavior.10

When ketamine is abused, it can produce more intense effects, with users reporting complete and utter detachment from their bodies. The experience of these effects, which are similar to those described by people who have had near-death experiences, has been described as being in the “K-hole.” The high produced by ketamine starts roughly two to five minutes after the dose has been smoked or swallowed, or about 30 seconds after injection, and lasts for about an hour. The first feeling of the high the user will get is an overwhelming sense of relaxation, sometimes described as a “full-body buzz.”7,10

Possible Mechanisms of Action for Depression
Traditional antidepressants such as selective serotonin reuptake inhibitors (eg, fluoxetine, sertraline, and escitalopram) and serotonin-norepinephrine reuptake inhibitors (eg, venlafaxine and duloxetine) work by increasing levels of the neurotransmitters serotonin, norepinephrine, and/or dopamine.5 However, ketamine’s antidepressant effects appear to be much different, with several theories existing to explain its possible mechanism of action.

Ketamine Glutamate Mechanism
Ketamine is an N-methyl-D-aspartate (NMDA) antagonist, meaning it blocks the activation of the NMDA receptor by the excitatory neurotransmitter glutamate. Evidence suggests that overexcitation by glutamate may cause shriveling of synaptic connections, leading to depression and other mood disorders. It appears ketamine increases neuronal spasticity with the formation of new connections between nerve cells in parts of the brain involved in emotion and mood.6 Because of concerns of potential abuse with ketamine, pharmacologists have also researched other NMDA receptor antagonists as alternatives to ketamine, including memantine, which is used to treat patients with Alzheimer’s disease. Clinical studies, however, have shown memantine doesn’t have the same antidepressant characteristics.10

Brain-Derived Neurotrophic Factor
To understand the differences between ketamine and memantine, a team of researchers examined the effect of ketamine and memantine on the hippocampal neurons of mice. They found key functional differences in how the drugs suppress NMDA receptor function at rest and how they inhibit the eukaryotic elongation factor 2 kinase signaling pathway. When the extracellular recording solution didn’t contain magnesium, both ketamine and memantine antagonized NMDA receptors. However, with the addition of magnesium, ketamine blocked NMDA receptors, while memantine didn’t. In addition, ketamine inhibited the phosphorylation of eukaryotic elongation factor 2 and augmented expression of brain-derived neurotrophic factor. Memantine didn’t produce these effects, leading to the belief that it’s the augmentation of brain-derived neurotrophic factor that makes ketamine an effective antidepressant.6

Opioid Theory
Some researchers believe there’s evidence that ketamine’s effectiveness against depression comes from its interaction with the brain’s opioid system, which controls pain, reward, and addictive behaviors. A Stanford University team reported its findings last year in the American Journal of Psychiatry. The study authors suggest ketamine acts as an opioid (eg, fentanyl and oxycodone), leading to its rapid effects.11

Ketamine-Inspired Medications
Ketamine’s potential as an antidepressant has stimulated additional research by two major pharmaceutical companies, Allergan and Janssen. Allergan is developing rapastinel, an IV drug with mechanism of action similar to ketamine in the brain, and anticipates FDA approval in 2020.12

Ketamine is a mixture of two enantiomers—mirror image molecules. Esketamine, the s-enantiomer of ketamine, is an NMDA receptor agonist that’s thought to help restore synaptic connections in brain cells in people with MDD.13 In March 2019, the FDA granted approval for esketamine (Spravato) to Janssen Pharmaceuticals under the Fast Track and Breakthrough Therapy designation. It’s the first new medication for treatment of TRD in decades.

The label for Spravato contains a boxed warning cautioning that patients are at risk for sedation and difficulty with attention, judgment, and thinking (dissociation); abuse and misuse; and suicidal thoughts and behaviors after administration of the drug. Because of the risk of sedation and dissociation, patients must be monitored by a health care provider for at least two hours after receiving their Spravato dose. The Risk Evaluation and Mitigation Strategies require both prescribers and patients to sign a patient enrollment form clearly stating that the patients understand they should make arrangements to safely leave the health care setting to get home and shouldn’t drive or use heavy machinery for the rest of the day on which they receive the drug. Additionally, Spravato must be dispensed with a patient medication guide that outlines the drug’s uses and risks.14

Esketamine is a Schedule III controlled substance self-administered by patients under the supervision of a health care provider in a certified doctor’s office or clinic, and the spray cannot be taken home. The health care providers instruct the patients about how to operate the nasal spray device. During and after each use of the nasal spray device, the health care providers check the patients and determine when they are ready to leave.13

Patients taking Spravato will receive an initial 56-mg dose followed by a dose (56 mg or 84 mg) twice weekly for weeks one to four. Maintenance dosing of 56 mg or 84 mg once weekly is continued for weeks five to eight. After eight weeks, patients continue to receive 56 mg or 84 mg every two weeks or once weekly depending on their response.14

According to the FDA, “The efficacy of esketamine was evaluated in three short-term (four-week) clinical trials and one longer-term maintenance-of-effect trial. In the three short-term studies, patients were randomized to receive esketamine or a placebo nasal spray. In light of the serious nature of TRD and the need for patients to receive some form of treatment, all patients in these studies started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. The primary efficacy measure was the change from baseline on a scale used to assess the severity of depressive symptoms. In one of the short-term studies, Spravato nasal spray demonstrated statistically significant effect compared with placebo on the severity of depression, and some effect was seen within two days. The two other short-term trials did not meet the prespecified statistical tests for demonstrating effectiveness. In the longer-term maintenance-of-effect trial, patients in stable remission or with stable response who continued treatment with Spravato plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than did patients on placebo nasal spray plus an oral antidepressant.”13

In the clinical trials, side effects of esketamine included nausea, vertigo, anxiety, sedation, dizziness, lethargy, vomiting, hypoesthesia, increased blood pressure, and feeling intoxicated. The FDA notes that higher risk for adverse cardiovascular or cebrovascular effects may exist for patients with a history of aneurysmal vascular disorders and those with poorly controlled or unstable hypertension. Patients are cautioned to get a night’s restful sleep after use before driving or operating machinery.

The FDA further cautions patients who are breastfeeding and who are or could become pregnant about possible fetal harm. “Women with reproductive potential should be cautioned to consider pregnancy planning and prevention, and women should not breast-feed while being treated.”13

Over the past two decades, there’s been minimal advancement in the treatment of depression and TRD. Evidence supporting ketamine’s efficacy for TRD along with its ability to help reduce suicide ideation and SIBs provides clinicians a much-needed treatment option.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in 10 states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Depression. World Health Organization website. https://www.who.int/news-room/fact-sheets/detail/depression. Updated March 22, 2018.

2. Major depression. National Institute of Mental Health website. https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Updated February 2019.

3. Brown J. 4 things we now know about treatment-resistant depression. Johnson & Johnson website. https://www.jnj.com/health-and-wellness/4-facts-about-treatment-resistant-depression. Published April 30, 2018.

4. In an old drug, new hope for depression. Scientific American. https://www.scientificamerican.com/custom-media/mount-sinai/in-an-old-drug-new-hope-for-depression/. Published October 19, 2018.

5. Monteggia LM, Zarate C Jr. Antidepressant actions of ketamine: from molecular mechanisms to clinical practice. Curr Opin Neurobiol. 2015;30:139-143.

6. Iadarola ND, Niciu MJ, Richards EM, et al. Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Ther Adv Chronic Dis. 2015;6(3):97-114.

7. Ketamine. Drugs.com website. https://www.drugs.com/illicit/ketamine.html. Updated November 5, 2018.

8. Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice. Acta Pharmacol Sin. 2016;37(7):865-872.

9. Fact file on ketamine. World Health Organization website. https://www.who.int/medicines/news/20160309_FactFile_Ketamine.pdf. Published March 2016.

10. Hallucinogens and dissociative drugs. National Institute on Drug Abuse website. https://www.drugabuse.gov/sites/default/files/rrhalluc.pdf

11. Ketamine’s antidepressive effects tied to opioid system in brain. Stanford Medicine News Center website. https://med.stanford.edu/news/all-news/2018/08/ketamines-antidepressive-effects-tied-to-opioid-system-in-brain.html. Published August 28, 2018.

12. Ketamine based drugs are on the horizon for TRD. Pharmaceutical Technology website. https://www.pharmaceutical-technology.com/comment/ketamine-based-drugs-horizon-trd/. Published October 5, 2018.

13. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. FDA website. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm. Updated March 5, 2019.

14. Spravato. Janssen website. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf. Updated May 2019.