Ketamine treatment for depression and other psychiatric disorders is gaining acceptance not only because of its efficacy, but also because of a growing awareness of its generally favorable safety profile. Widespread use of ketamine in the medical and veterinary field over the last 5 decades helps attest to its tolerability. Given ketamine's new role in the field of psychiatry, psychiatrists administering intravenous (IV) ketamine need to be aware of the significant drug effects that can occur during and after administration.
History of Ketamine
Ketamine, an arylcyclohexylamine, was first synthesized in 1962 by American scientist Calvin Stevens while he was consulting for Parke-Davis Laboratories (Detroit, MI).1 The history of ketamine, for medical purposes, began as a replacement anesthetic for phencyclidine (PCP), which typically causes more severe psychotomimetic side effects that are less transient given the longer half-life of PCP. In 1963, ketamine was patented in Belgium.1 Testing on humans by Dr. Edward Domino began in 1964, and it was noted that ketamine produced only minor hallucinogenic side effects. Dr. Domino's wife, Toni, later coined the term “dissociative anesthetic.2” Domino et al.3 published the first report of human use in 1965, followed by the filing of a US patent for human and animal use in 1966, and the commercial preparation of ketamine hydrochloride in 1969. This formulation, and most others marketed as generic ketamine, are a racemic mixture of both the S(+) and R(−) isomers.4
In 1970, the US Food and Drug Administration (FDA) approved ketamine for human use, and it was then literally battle-tested when administered to soldiers during the Vietnam War on the battlefield who required surgical interventions or immediate pain control.2 Ketamine spent much of the next 30 years as an anesthetic agent in operating rooms, emergency departments, or intensive care units. However, in the late 1990s, research on ketamine began elucidating its potential as an antidepressant.4
Use of Ketamine in Medical Specialties
Ketamine is commonly used in the fields of anesthesia and pain management, emergency medicine, and neurology. In anesthesiology, ketamine is used to induce general anesthesia (1–2 mg/kg IV push), and is used in patients with hypotension, shock, or severe reactive airway disease. Ketamine is a bronchodilator and sympathetic stimulant and thus is useful in patients with these conditions. In addition, ketamine is commonly used as analgesia for burn victims undergoing repeated, daily dressing changes.5
In the emergency department, ketamine is employed as the preferred anesthetic in minor procedures in both adult and pediatric patients, and as an adjunctive treatment to decrease opiate burden in the acute care setting. In a prospective, observational study of adult patients with severe pain at an urban public hospital, Ahern et al.6 showed that low-dose ketamine (15 mg IV) combined with a reduced dose of hydromorphone (0.5 mg IV) produced rapid, profound pain relief without significant side effects.6 For major depressive disorder (MDD), acute suicidal ideation, and other psychiatric disorders such as posttraumatic stress disorder and obsessive-compulsive disorder, most studies have employed a protocol of 0.5 mg/kg IV administered over 40 minutes.7 In general, this is one-half to one-quarter of the dose given to induce general anesthesia via IV push. Respiratory arrest and loss of consciousness are uncommon at subanesthetic doses.5
Route of Administration
The most robust ketamine studies to date have all used the IV route of administration to treat depression. Some other common routes of ketamine administration in order of increasing bioavailability are as follows: oral, intranasal, and intramuscular (IM) (Table 1).8–10 By definition, IV administration yields 100% bioavailability. As would be expected, dosing precision and accuracy decrease as bioavailability does due to individual variabilities in mucosal absorption and first pass effect. Although IM has only a slightly lower bioavailability compared to IV, rate control and dose titration cannot be employed and, thus, the risk of prolonged dissociation, nausea, or elevated blood pressure increases. Although the IV route comes with increased risk of bloodstream infection, a 40-minute infusion is associated with less risk than a continuous IV with longer dwell time (more often found in the inpatient setting).11
Ketamine Bioavailabilities by Route of Administration
Common Side Effects with Ketamine Administration for Psychiatric Conditions
Like all medications, there are side effects with ketamine infusions, but the side effects are typically transient and occur primarily during the course of the infusion.
In 2015, Wan et al.7 published a retrospective chart review of patients undergoing ketamine infusions (for MDD) in three clinical trials conducted at two academic medical centers. Ninety-seven patients with MDD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition,12 received a total of 205 IV ketamine infusions at 0.5 mg/kg over the course of 40 minutes. Comparable to even more recent studies, the response rate was 67%. The most common side effects during the infusions (in order of occurrence) were feeling drowsy or sleepy, dizziness/faintness, poor coordination/unsteadiness, dizziness when standing up, blurred vision, feeling strange or unreal, abnormal sensations, slurred speech, headache, dry mouth, trouble concentrating, numbness or tingling, and a diminished mental capacity. These side effects generally resolved within 4 to 24 hours after each infusion.7 For this reason, patients are typically prohibited from driving on the same day.
As a sympathomimetic drug, ketamine may cause transient increases in heart rate and blood pressure. Wan et al.7 found that mean peak systolic blood maximally increased 16% from baseline and the mean peak diastolic blood pressure maximally increased 18% from baseline. Blood pressure returned to baseline within 4 hours after the infusion.7
Neuropsychiatric Drug Effects Associated with Ketamine
The question of whether ketamine treatment causes neurocognitive deficits is generally dependent on the dose and frequency as well as time point of measurement. Krystal et al.13 first demonstrated that patients can experience impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test while receiving subanesthetic IV ketamine. Cognitive impairment was dose dependent and rapidly declined after the termination of the infusion.13 Other studies have attempted to longitudinally measure potential cognitive deficits after ketamine infusion as opposed to during infusion. In a double-blind study with an active placebo, Murrough et al.14 demonstrated that patients had no adverse neurocognitive effects when comparing MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery scores 1 week after a single 0.5 mg/kg ketamine infusion. Another study by Diamond et al.15 found no evidence of deficits in memory performance up to 26 weeks after the last of 3 to 6 ketamine infusions that were administered over 3 weeks.
Murrough et al.14 and Shiroma et al.16 both found that lower cognitive scores at baseline, likely symptomatic of depression, were predictive for a positive response to ketamine; in particular, patients with slower processing speed and increased inattention were more likely to respond. As opposed to deficits, Shiroma et al.16 found a significant improvement in scores of visual memory and complex working memory after the last of six ketamine infusions dosed at 0.5 mg/kg 3 times per week over 12 days, this improvement was accounted for by improvement of depressive symptoms.
Subanesthetic doses rarely cause psychotomimetic side effects in healthy volunteers for more than 90 minutes after infusion. Lahti et al.17 demonstrated that when ketamine was administered to schizophrenia patients, the Brief Psychiatric Rating Scale (inclusive of psychosis) increased at 20 minutes but not at 90 or 180 minutes after infusion. However, ketamine is contraindicated for use in schizophrenia and other psychotic disorders given that use over 1 year has demonstrated worsening delusions that may persist after ketamine discontinuation. Furthermore, outstanding evidence suggests that patients carrying alleles that predispose them to psychosis are more likely to experience ketamine-induced psychosis.18
Chronic illicit ketamine abuse is more likely to lead to psychosis and cognitive deficits (particularly memory deficits) given the typically higher and more frequent use.19 Chronic ketamine users are also more likely to abuse ketamine with other drugs, such as 3,4-Methylenedioxymethamphetamine, which is also known to have a psychotomimetic side-effect profile.18 In the clinical setting, urine toxicology screens are useful for patient screening and monitoring, especially in patients with a past history of substance abuse disorders.20 However, and importantly, Wan et al.7 were able to phone-interview 46 patients at a mean time of 2.9 ± 1.9 years from their last ketamine infusion and found that no patients reported increased cravings, use of ketamine, or other illicit substances.
Considering the side effects seen in chronic ketamine use, one critique of ketamine treatment for treatment-refractory depression is the paucity of evidence in treating patients indefinitely on maintenance regimens. Although further long-term cognitive data are being collected on this patient population, the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments published recommendations advising against prescription of at-home self-administration of ketamine and discontinuation of ketamine treatment for those patients who cannot adhere to no more than one dose per week by the second month of treatment.20
After an anesthetic dose of ketamine, electroencephalography (EEG) shows a classic “gamma burst” EEG pattern with alternating slow delta and gamma waves. Additionally, theta waves increase and alpha/beta waves decrease.21
Although there is mixed evidence regarding pro and antiepileptic effects of ketamine in case studies, clinical studies have demonstrated that ketamine at anesthetic doses neither precipitates nor aggravates seizures in patients with epilepsy.22 In fact, one retrospective study showed a termination of refractory status epilepticus in all 11 patients identified as treated with ketamine.23
As would be expected, Duncan et al.24 found that ketamine increased slow wave activity (SWA) in patients who are depressed 1 day after ketamine treatment. However, this same benefit was not found for bipolar depression. Moreover, SWA activity correlated with brain-derived neurotrophic factor (BDNF) levels in depressed patients, and both SWA and BDNF trended back to baseline day 2 postketamine treatment, whereas total sleep increased through day 2. Patients with low SWA and BDNF at baseline, followed by increases after the ketamine infusion, were more likely to achieve response.24
Urologic Side Effects Associated with Ketamine Use/Abuse
Ketamine can cause genitourinary dysfunction, especially urothelial dysfunction. This dysfunction can mimic, although it is histologically distinct from, bladder pain syndrome/interstitial cystitis.25 These and other genitourinary side effects have been noted primarily in illicit ketamine abusers, rather than patients receiving ketamine in the clinical setting. Lin et al.26 studied 36 ketamine-induced cystitis (KC) patients who had a mean daily ingestion of 4,750 mg of ketamine over an average of 3.56 years. After cystoscopic biopsies, they concluded that microvascular injury and alteration of bladder endothelial cells could be a major cause of KC-induced bladder dysfunction.26 Unfortunately, the treatment for ketamine-associated urogenital dysfunction is supportive with no true antidote for the damage of endothelial cells.
Tachyphylaxis and Ketamine Therapy
Whether tachyphylaxis, the acute diminished response to successive doses, exists and to what degree remains to be studied in a systematic way. Messer and Haller27 describe a case study of a 46-year-old woman with MDD who had a successful response to repeated ketamine infusions over a 15-month period with no tachyphylaxis noted during this time.
In the medical literature there are a few isolated case studies that indict ketamine as the culprit of allergic reactions. Mathieu et al.28 describes a 3-year-old who developed an extensive macular rash after ketamine administration. A Prausnitz-Kutzner (P-K) test demonstrated that the histamine release was not the result of an anaphylactic reaction, but rather a direct pharmacological effect of the drug.
Once considered a drug only used in veterinary medicine, anesthesiology, and pain management, ketamine is now considered by many to be a novel-acting drug for treating depression and suicidal ideation. As ketamine infusion therapy continues to show successful results for many patients, understanding all of the potential side effects becomes critical for providers to limit risk while providing appropriate applications.
- Rogers K. Ketamine. https://www.britannica.com/science/ketamine. Accessed March 23, 2018.
- Domino EF. Taming the ketamine tiger. Anesthesiology. 2010;113(3):678–684. doi:10.1097/ALN.0b013e3181ed09a2 [CrossRef].
- Domino EF, Chodoff P, Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic in man. Clin Pharmacol Ther. 1965;6:279–291. doi:10.1002/cpt196563279 [CrossRef]
- Vlisides L, Li PE. Ketamine: 50 years of modulating the mind. Front Hum Neurosci. 2016;10:612. doi:10.3389/fnhum.2016.00612 [CrossRef].
- Kurdi MS, Theerth KA, Deva RS. Ketamine: current applications in anesthesia, pain, and critical care. Anesth Essays Res.2014;8(3):283–290. doi:. doi:10.4103/0259-1162.143110 [CrossRef]
- Ahern TL, Herring AA, Stone MB, Frazee BW. Effective analgesia with low-dose ketamine and reduced dose hydromorphone in ED patients with severe pain. Am J Emerg Med.2013;31(5):847–851. doi:. doi:10.1016/j.ajem.2013.02.008 [CrossRef]
- Wan LB, Levitch CF, Perez AM, et al. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry.2015;76(3):247–252. doi:. doi:10.4088/JCP.13m08852 [CrossRef]
- Chong C, Schug SA, et al. Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: preliminary findings from a three-way randomized, crossover study. Clin Drug Investig.2009;29(5):317–324. doi:. doi:10.2165/00044011-200929050-00004 [CrossRef]
- Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci.1982;71(5):539–542. doi:10.1002/jps.2600710516 [CrossRef]
- Yanagihara Y, Ohtani M, Kariya S, et al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos.2003;24(1):37–43. doi:. doi:10.1002/bdd.336 [CrossRef]
- Cheung E, Baerlocher MO, et al. Venous access: a practical review for 2009. Can Fam Physician.2009;55(5):494–496.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Publishing; 1994.
- Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry.1994;51(3):199–214. doi:10.1001/archpsyc.1994.03950030035004 [CrossRef]
- Murrough JW, Burdick KE, Levitch CF, et al. Neurocognitive effects of ketamine and association with antidepressant response in individuals with treatment-resistant depression: a randomized controlled trial. Neuropsychopharmacology.2015;40(5):1084–1090. doi:. doi:10.1038/npp.2014.298 [CrossRef]
- Diamond PR, Farmery AD, Atkinson S, et al. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. J Psychopharmacol.2014;28(6):536–544. doi:. doi:10.1177/0269881114527361 [CrossRef]
- Shiroma PR, Albott CS, Johns B, Thuras P, Wels J, Lim KO. Neurocognitive performance and serial intravenous subanesthetic ketamine in treatment-resistant depression. Int J Neuropsychopharmacol.2014;17(11):1805–1813. doi:. doi:10.1017/S1461145714001011 [CrossRef]
- Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001;25:455–467. doi:10.1016/S0893-133X(01)00243-3 [CrossRef](01)00243–3.
- Xu K, Lipsky RH. Repeated ketamine administration alters N-methyl-D-aspartic acid receptor subunit gene expression: implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans. Exp Biol Med (Maywood).2015;240(2):145–155. doi:. doi:10.1177/1535370214549531 [CrossRef]
- Morgan CJA, Riccelli M, Maitland CH, Curran HV. Long-term effects of ketamine: evidence for a persisting impairment of source memory in recreational users. Drug Alcohol Depend. 2004;75:301–308. doi:. doi:10.1016/j.drugalcdep.2004.03.006 [CrossRef]
- Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry.2017;74(4):399–405. doi:. doi:10.1001/jamapsychiatry.2017.0080 [CrossRef]
- Akeju O, Song AH, Hamilos AE, et al. Electroencephalogram signatures of ketamine anesthesia-induced unconsciousness. Clin Neurophysiol.2016;127(6):2414–2422. doi:. doi:10.1016/j.clinph.2016.03.005 [CrossRef]
- Celesia GG, Chen RC, Bamforth BJ. Effects of ketamine in epilepsy. Neurology.1975;25(2):169–172. doi:10.1212/WNL.25.2.169 [CrossRef]
- Synowiec AS, Singh DS, Yenugadhati V, Valeriano JP, Schramke CJ, Kelly KM. Ketamine use in the treatment of refractory status epilepticus. Epilepsy Res. 2013;105(1–2):183–188. doi:. doi:10.1016/j.eplepsyres.2013.01.007 [CrossRef]
- Duncan WC, Zarate CA Jr, . Ketamine, sleep, and depression: current status and new questions. Curr Psychiatry Rep. 2013;15(9):394. doi:. doi:10.1007/s11920-013-0394-z [CrossRef]
- Myers FA, Bluth M, Cheung W. Ketamine: A cause of urinary tract dysfunction. Clin Lab Med. 2016;36:721–744. doi:. doi:10.1016/j.cll.2016.07.008 [CrossRef]
- Lin CC, Lin AT, Yang AH, Chen KK. Microvascular injury in ketamine-induced bladder dysfunction. PLoS One. 2016;11(8):e0160578. doi:. doi:10.1371/journal.pone.0160578 [CrossRef]
- Messer MM, Haller IV. Maintenance ketamine treatment produces long-term recovery from depression. Prim Psychiatry.2010;17(4):48–50.
- Mathieu A, Goudsouzian N, Snider MT. Reaction to ketamine: anaphylactoid or anaphylactic?Br J Anaesth.1975;47(5):624–627. doi:. doi:10.1093/bja/47.5.624 [CrossRef]
Ketamine Bioavailabilities by Route of Administration
|Route of Administration