Ketamine Nasal Spray

Ketamine, C13H16ClNO, is a synthetic racemic mixture of R-ketamine and S-ketamine (esketamine).^[1][2][3] Ketamine is a derivative of phencyclidine (PCP) and is considered a DEA Schedule III controlled substance.^[4][1]

Ketamine was first FDA approved in 1970 under the brand name Ketalar, and is commonly used as an anaesthetic for both pediatric and adult surgical procedures.^[5][6][7]

Ketamine is not FDA approved for depression, but esketamine (S-ketamine), the S(+) enantiomer of ketamine, is. In 2019, the FDA approved Spravato (esketamine) nasal spray, in conjunction with an oral antidepressant medication, to treat adults with treatment-resistant depression and depressive symptoms in adults with major depressive disorder (MDD) with suicidal thoughts or actions.^[8] Esketamine nasal spray is only available with a prescription and through a restricted Risk Evaluation and Mitigation Strategy program that is strictly implemented and monitored by a licensed healthcare provider. Esketamine nasal spray is not FDA approved as an anesthetic agent.^[9]

Ketamine is a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist.^[10] Inhibition of NMDA receptors on GABA neurons results in disinhibition of dopaminergic neurons and therefore increased dopamine release.^[11]

Ketamine is an opioid receptor agonist and an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activator.^[12] It is a transport inhibitor of the D-serine receptor and an HCN1 receptor inhibitor.^[13][14][15]

Ketamine increases the number of serotonin 1B receptors.^[16] It is an uptake inhibitor of norepinephrine, serotonin, and Dopamine receptors.^[13]

Ketamine may increase levels of brain-derived neurotrophic factor (BDNF) via synaptogenesis that occurs through increased glutamate levels.^[14]

Ketamine is identified as a Schedule III controlled substance under the Controlled Substances Act and therefore has a low to moderate risk of psychological and physical dependence.^[9][27] Physicians should carefully analyze an individuals risk of substance dependency, including alcohol, before prescribing and administering intranasal ketamine and should continuously monitor patients for signs of psychological and physical dependence throughout the treatment course.

Ketamine is contraindicated in patients with schizophrenia. Ketamine may increase symptoms of psychosis and may exacerbate the symptoms of schizophrenia.^[14]

Intranasal ketamine is contraindicated for patients with severe hepatic impairment.^[23]

Esketamine nasal spray causes a temporary increase of blood pressure and is therefore contraindicated in patients with hypertension. Esketamine nasal spray is contraindicated in patients with conditions that, with an increase in blood pressure, pose a serious health risk, including aneurysmal vascular disease, history of intracerebral hemorrhage, and arteriovenous malformation).^{[8][28][29][9]}

Ketamine is a controlled substance that has the potential for dependence (physical and psychological) and abuse.^[4][1] Patients with a history of drug and/or alcohol abuse should not use ketamine. Physicians should assess patients for the risk of abuse and misuse before prescribing esketamine nasal spray. Physicians should monitor patients for signs of abuse throughout the treatment program.

Esketamine nasal spray is not for use in children. Patients who are allergic to ketamine, esketamine, or any of the excipients should not take esketamine nasal spray. Patients should avoid the use of alcohol with ketamine.^[9]

The use of intranasal esketamine in conjunction with psychostimulants monoamine oxidase inhibitors (MAOIs) may increase blood pressure.^[23] Physicians should closely monitor blood pressure in patients who are taking psychostimulants, including amphetamines, methylphenidate, stimulant weight-loss medications, modafanil, and armodafinil, as well as patients taking MAOIs including tranylcypromine, phenelzine, isocarboxazid, and selegiline.^[9][32]

Intranasal esketamine may increase the sedative effects of central nervous system (CNS) depressants. Physicians should closely monitor for sedation in patients who are taking CNS depressants, including benzodiazepines, opioids, and alcohol.^[9][23]

Benzodiazepines may reduce the antidepressant effect of ketamine.^[26]

The most common symptoms associated with esketamine nasal spray include dizziness, nausea, sedation, lethargy, disassociation, vertigo, hypoesthesia, anxiety, increased blood pressure, vomiting, and feeling drunk.^[8][9] Physicians should closely monitor patients for at least two hours following administration.

Ketamine increases blood pressure and heart rate.^[7][33] Physicians should monitor blood pressure before administration and for at least two hours following administration.

In some cases, antidepressant agents increase the risk of suicidal thoughts and actions in young adults, especially during the initial treatment period. Esketamine nasal spray may increase suicidal thoughts and actions, especially in patients with a history (or family history) of depression.^[34][9] Physicians should closely monitor patients for worsening of depressive symptoms.

Ketamine is a controlled substance that has the potential for dependence (physical and psychological) and abuse.^[1] Physicians should assess patients for the risk of abuse and misuse before prescribing esketamine nasal spray. Physicians should monitor patients for signs of abuse throughout the treatment program.

This is not an all inclusive list of the side effects of esketamine nasal spray. Side effects are typically felt shortly after administering esketamine nasal spray and generally resolve the same day.

Chronic misuse of ketamine has been associated with impaired cognitive processing speed, verbal fluency, verbal learning, verbal memory, and visual recognition memory.^[35]

Ketamine use during pregnancy can harm the fetus. One study noted the effects of ketamine on a newborn baby whose mother was suspected of continuing to abuse ketamine during pregnancy. Researchers found high levels of ketamine in the newborn’s hair and observed low birth weight, general hypotonia, moderate cerebral dysfunction, intrauterine growth retardation, and poor reflex responses in the newborn.^[30] A study conducted on rats showed that ketamine administered to pregnant rats impaired neuronal development in pups (offspring).^[31] Women who are planning a pregnancy or who are pregnant should not take esketamine nasal spray.^[9]

Women who are breastfeeding should not take ketamine.^[8]

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1. NIH National Library of Medicine. Ketamine. PubChem. Publication Date Unknown. Accessed online at: https://pubchem.ncbi.nlm.nih.gov/compound/Ketamine.
2. Andrade C. Ketamine for Depression, 3: Does Chirality Matter? J Clin Psychiatry 2017;78:e674.
3. Yang C, Shirayama Y, Zhang JC, et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Translational Psychiatry. 2015;5:632.
4. Chang F, Xu K, Huang MCH, and Krystal JH. Alcohol Triggers Re-emergence of Ketamine-Like Experience in A Ketamine Ex-user. J Clin Psychopharmacol. 2017;37(1):110-112.
5. Ketalar (1970). “U.S. food and drug administration, center for drug evaluation and research,” in Label and Approval History. Accessed online at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist
6. Li L and Vlisides PE. Ketamine: 50 Years of Modulating the Mind. Front Hum Neurosci. 2016;10: 612.
7. Suleiman ZA, Kolawole IK, and Bolaji BO. Evaluation of the Cardiovascular Stimulation Effects After Induction of Anaesthesia with Ketamine. J West Afr Coll Surg. 2012; 2(1):38-52.
8. Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. March 05, 2019. Accessed online at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified.
9. Highlights of Prescribing Information. SPRAVATO™ (esketamine) nasal spray, CIII. Accessed online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf.
10. Krystal JH, Sanacora G, Duman RS. Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry. 2013;73:1133-1341.
11. Liu Y, Lin D, Wu B, Zhou W. Ketamine abuse potential and use disorder. Brain Research Bulletin. 2016;126(1):68-73.
12. Thase M and Connolly R. Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects. Up To Date. Updated August 26, 2020. Accessed online at: https://www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects.
13. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol Rev. 2018;70(3):621–660.
14. Rosenbaum SB, Gupta V, and Palacios JL. Ketamine. StatPearls [Internet]. Updated October 5, 2020.
15. Chen X, Shu S, Bayliss DA. HCN1 Channel Subunits Are a Molecular Substrate for Hypnotic Actions of Ketamine. J Neurosci. 2009;29(3):600–609.
16. Tiger M, Veldman ER, Ekman CJ, Halldin C, Svenningsson P and Lundberg J. A randomized placebo controlled PET study of ketamine’s effect on serotonin 1B receptor binding in patients with SSRI resistant depression. Translational Psychiatry. 2020;10(159).
17. United States Drug Enforcement Administration. Drug Scheduling. Accessed online at https://www.dea.gov/drug-scheduling.
18. Bahr R, Lopez A, Rey JA. Intranasal Esketamine (SpravatoTM) for Use in Treatment-Resistant Depression In Conjunction With an Oral Antidepressant. P T. 2019;44(6): 340-342, 344-346, 375.
19. Riva-Posse P, Reiff CM, Edwards JA, et al. Blood pressure safety of subanesthetic ketamine for depression: A report on 684 infusions. J Affect Disord. 2018;236:291-297.
20. Lafferty KA and Schraga ED. What are the negative effects of ketamine in the induction stage of tracheal intubation? MedScape. Jan 15, 2019. Accessed online at: https://www.medscape.com/answers/109739-91174/what-are-the-negative-effects-of-ketamine-in-the-induction-stage-of-tracheal-intubation.
21. Su PH, Chang YZ, and Chen JY. Infant With In Utero Ketamine Exposure: Quantitative Measurement of Residual Dosage in Hair. Pediatrics & Neonatology. 2010;51(5):279-84.
22. Zhao T, Li C, Wei W, et al. Prenatal ketamine exposure causes abnormal development of prefrontal cortex in rat. Sci Rep. 2016;6:26865.
23. Laban TS and Saadabadi A. Monoamine Oxidase Inhibitors (MAOI). StatPearls [Internet]. Updated August 22, 2020.
24. Andrade, Chittaranjan. Ketamine for Depression, 5:Potential Pharmacokinetic and Pharmacodynamic Drug Interactions. J Clin Psychiatry. 2017;78(7):e858-e861.
25. Liebe T, Li S, Lord A, et al. Factors Influencing the Cardiovascular Response to Subanesthetic Ketamine: A Randomized, Placebo-Controlled Trial. Int J Neuropsychopharmacol. 2017;20(11):909-918.
26. Nischal A, Tripathi A, Nischal A, and Trivedi JK. Suicide and Antidepressants: What Current Evidence Indicates. Mens Sana Monogr. 2012;10(1):33-44.
27. Chan KWS, Lee TMC, Siu AMH, et al. Effects of chronic ketamine use on frontal and medial temporal cognition. Addictive Behaviors. 2013;38(5):2128-2132.