Ketamine

For the functional group referred to as ketimine, see imine.
Ketamine
Systematic (IUPAC) name
(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
Clinical data
AHFS/Drugs.com Consumer Drug Information
Licence data US FDA:link
  • AU: B3
  • US: C (Risk not ruled out)
Moderate
IV, IM, Insufflated, oral, topical
Pharmacokinetic data
Metabolism Hepatic, primarily by CYP3A4[1]
Half-life 2.5–3 hours
Excretion renal (>90%)
Identifiers
6740-88-1 Yes
N01AX03
PubChem CID 3821
DrugBank DB01221 Yes
ChemSpider 3689 Yes
UNII 690G0D6V8H Yes
KEGG D08098 Yes
ChEBI CHEBI:6121 Yes
ChEMBL CHEMBL742 Yes
Chemical data
Formula C13H16ClNO
237.725 g/mol
Physical data
Melting point 262 °C (504 °F)
 Yes (what is this?)  (verify)

Ketamine (INN) is a medication used mainly for starting and maintaining anesthesia. Other uses include sedation in intensive care, as a pain killer, as treatment of bronchospasm, as a treatment for complex regional pain syndrome and as an antidepressant. It induces a trance like state while providing pain relief, sedation, and memory loss.[2] Heart function, breathing and airway reflexes generally remain functional.[2]

Common side effects include a number of psychological reactions as the medication wears.[3] This may include agitation, confusion and psychosis among others.[3][4] Elevated blood pressure and muscle tremors are relatively common, while low blood pressure and a decrease in breathing is less so.[3][4] Spasms of the larynx may rarely occur.[3]

Pharmacologically, ketamine is classified as an NMDA receptor antagonist, but it also acts at numerous other sites (including opioid receptors and monoamine transporters).[5] Like other drugs in its class, such as phencyclidine (PCP), it is classified as a dissociative agent.[6]

Ketamine was first developed in 1962.[7] It is on the WHO Model List of Essential Medicines, a list of essential medicines that should be available in a health system.[8] Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Its use as a recreational drug has been associated with several high-profile deaths.[9]

Use

One 10-ml vial of 1000 mg of ketamine

Anesthesia

Uses as an anaesthetic:

Since it suppresses breathing much less than most other available anaesthetics,[10] ketamine is used in medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available.

Ketamine is frequently used in severely injured people and appears to be safe in this group.[11] A 2011 clinical practice guideline supports the use of ketamine as a dissociative sedative in emergency medicine.[2] It is the drug of choice for people in traumatic shock who are at risk of hypotension.[12] Low blood pressure is harmful in people with severe head injury[13] and ketamine is least likely to cause low blood pressure, often even able to prevent it.[14][15]

The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. When used at anesthetic doses, it will usually stimulate rather than depress the circulatory system.[16] It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is considered relatively safe because protective airway reflexes are preserved.[17]

Ketamine is used as a bronchodilator in the treatment of severe asthma.[18] However, evidence of clinical benefit is limited.[18][19]

Pain

Ketamine may be used for postoperative pain management. Low doses of ketamine reduces morphine use and nausea and vomiting after surgery.[20] High quality evidence in acute pain is insufficient to determine if ketamine is useful in this situation.[21]

It may also be used as an intravenous analgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic. It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain. At these doses, the psychotropic side effects are less apparent and well managed with benzodiazepines.[22] Ketamine is an analgesic that is most effective when used alongside a low-dose opioid; as while it does have analgesic effects by itself, the higher doses required can cause disorienting side effects.[22] A review article in 2013 concluded, "despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain".[23]

Low-dose ketamine is sometimes used in the treatment of complex regional pain syndrome (CRPS).[24] A 2013 systematic review found only low-quality evidence to support the use of ketamine for CRPS.[25]

Depression

Ketamine has been tested in treatment-resistant bipolar depression, major depressive disorder, and people in a suicidal crisis in emergency rooms.[26] Benefit is often of a short duration.[27] The quality of the evidence supporting benefit, however, is generally low.[27]

The drug is given by a single intravenous infusion at doses less than those used in anesthesia, and preliminary data have indicated it produces a rapid (within 2 hours) and relatively sustained (about 1–2 weeks long) significant reduction in symptoms in some patients.[28] Initial studies with ketamine have sparked scientific and clinical interest due to its rapid onset,[29] and because it appears to work by blocking NMDA receptors for glutamate, a different mechanism from most modern antidepressants that operate on other targets.[27][30]

Recreational use

Ketamine poured onto glass and left to dry

Unlike the other well-known dissociatives PCP and DXM, ketamine is very short-acting. It takes effect within about 10 minutes,[31] while its hallucinogenic effects last 60 minutes when insufflated or injected and up to two hours when ingested orally.[32]

At subanesthetic doses, ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world which is known as depersonalization and derealization.[33] At sufficiently high doses, users may experience what is called the "K-hole", a state of extreme dissociation with visual and auditory hallucinations.[34] John C. Lilly, Marcia Moore and D. M. Turner (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with ketamine.[35] Both Moore and Turner died prematurely (due to hypothermia and drowning respectively) during presumed unsupervised ketamine use.[9]

Side effects

Ketamine is generally safe in those who are critically ill.[36]

Side effects may include one or more of the following:[37]

Emergence reactions manifest as vivid dreams, hallucinations, and delirium and occur in 10 to 20% of patients at anesthetic doses.[39] These reactions are less common in patients less than 15 years old and greater than 65 years old and when administered intramuscularly. Emergence reactions can occur up to 24 hours postoperatively. The chance of this occurring can be reduced by minimizing stimulation to the patient during recovery and pretreating with a benzodiazepine. If given a benzodiazepine, a lower dose of ketamine than normal should be given. Patients who experience severe reactions may require treatment with a small dose of a short- or ultrashort-acting barbiturate.[37]

Tonic-clonic movements are reported at higher anesthetic doses in greater than 10% of patients.[40]

Neurological effects

In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes in two small areas of the rat brain, which, however, has significant differences in metabolism from the human brain, so may not occur in humans.[41]

The first large-scale, longitudinal study of ketamine users found current frequent (averaging 20 days/month) ketamine users had increased depression and impaired memory by several measures, including verbal, short-term memory, and visual memory. Current infrequent (averaging 3.25 days/month) ketamine users and former ketamine users were not found to differ from controls in memory, attention, and psychological well-being tests. This suggests the infrequent use of ketamine does not cause cognitive deficits, and that any deficits that might occur may be reversible when ketamine use is discontinued. However, abstinent, frequent, and infrequent users all scored higher than controls on a test of delusional symptoms.[42]

Short-term exposure of cultures of GABAergic neurons to ketamine at high concentrations led to a significant loss of differentiated cells in one study, and noncell-death-inducing concentrations of ketamine (10 μg/ml) may still initiate long-term alterations of dendritic arbor in differentiated neurons. The same study also demonstrated chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal maintenance and development.[43][44]

More recent studies of ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents. One such study administered daily ketamine doses consistent with typical recreational doses (1 mg/kg IV) to adolescent cynomolgus monkeys for varying periods of time.[45] Decreased locomotor activity and indicators of increased cell death in the prefrontal cortex were detected in monkeys given daily injections for six months, but not those given daily injections for one month.[45] A study conducted on rhesus monkeys found a 24-hour intravenous infusion of ketamine caused signs of brain damage in five-day-old but not 35-day-old animals.[46] Some neonatal experts do not recommend the use of ketamine as an anesthetic agent in human neonates because of the potential adverse effects it may have on the developing brain. These neurodegenerative changes in early development have been seen with other drugs that share the same mechanism of action of NMDA receptor antagonism as ketamine.[47]

The acute effects of ketamine cause cognitive impairment, including reductions in vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.[48]

Urinary tract effects

A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from ketamine abuse.[49] Urinary tract symptoms have been collectively referred as "ketamine-induced ulcerative cystitis" or "ketamine-induced vesicopathy", and they include urge incontinence, decreased bladder compliance, decreased bladder volume, detrusor overactivity, and painful haematuria (blood in urine). Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases.[49][50] The pathogenesis of papillary necrosis has been investigated in mice, and mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence has been suggested as a possible mechanism.[51]

The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use corresponds linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 g/day reported symptoms of the lower urinary tract.[49] Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug for an extended period of time.[50] These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.[50]

Management of these symptoms primarily involves ketamine cessation, for which compliance is low. Other treatments have been used, including antibiotics, NSAIDs, steroids, anticholinergics, and cystodistension.[49] Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some patients, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulfate, or both. Further follow-up is required to fully assess the efficacy of these treatments.[49]

Liver problems

In case reports of three patients treated with (S)-(+)-ketamine for relief of chronic pain, liver enzyme abnormalities occurred following repeat treatment with ketamine infusions, with the liver enzyme values returning below the upper reference limit of normal range on cessation of the drug. The result suggests liver enzymes must be monitored during such treatment.[52]

Interactions

Other drugs which increase blood pressure may interact with ketamine in having an additive effect on blood pressure including: stimulants, SNRI antidepressants, and MAOIs. Increase blood pressure and heart rate, palpitations, and arrhythmias may be potential effects.

Ketamine may increase the effects of other sedatives, including, but not limited to: alcohols,[53] benzodiazepines,[54] opioids,[55] and barbiturates.[56]

Pharmacology

Administration

In medical settings, ketamine is usually injected intravenously or intramuscularly.[57]

Ketamine can be started using the oral route, or people may be changed from a subcutaneous infusion once pain is controlled. Bioavailability of oral ketamine hydrochloride is around 20%

As part of a cream, gel, or liquid (only available from compounding pharmacies, as it is not a branded product, specific formulation and ratios are specified by the prescribing physician) for topical application for nerve pain. Other ingredients found useful by pain specialists and their patients, as well as the compounding pharmacists who make the topical mixtures, include amitriptyline, cyclobenzaprine, clonidine, tramadol, gabapentin, baclofen, and mepivacaine and other longer-acting local anaesthetics (e.g. tetracaine, procaine).

Pharmacodynamics

Ketamine acts primarily as an antagonist of the NMDA receptor, and this action accounts for most of its effects.[5] However, the complete pharmacology of ketamine is more complex, and it is known to directly interact with a variety of other sites to varying degrees.[5] Known actions of ketamine include:

Ketamine appears to inhibit the NMDAR by binding both in the open channel and at an allosteric site.[64] The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively.[65]

Effects in central nervous system

NMDAR antagonism is responsible for the anesthetic, amnesic, dissociative, and hallucinogenic effects of ketamine, although activation of κ-opioid receptors and possibly sigma and mACh receptors may also contribute to its psychotomimetic properties.[5] Dopamine reuptake inhibition is likely to underlie the euphoria the drug produces, although an additional involvement of μ-opioid receptor activation cannot be excluded.[5] NMDAR antagonism is responsible for the rapid antidepressant effects of ketamine at lower doses.[66]

NMDAR antagonism results in analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine's actions interfere with pain transmission in the spinal cord.[40] Inhibition of nitric oxide synthase lowers the production of nitric oxide – a neurotransmitter involved in pain perception, hence further contributing to analgesia.[67] The action of ketamine at sigma and μ-opioid receptors is relatively weak, and evidence is mixed as to whether the latter is of significance to its analgesic effects.[5][68]

Ketamine also interacts with a host of other targets to cause analgesia. In particular, it blocks voltage-dependent calcium channels and sodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it inhibits the reuptake of serotonin and norepinephrine, which are involved in descending antinociceptive pathways.[40][69]

Effects in peripheral systems

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:[67]

Pharmacokinetics

Ketamine is absorbable by intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities.[67] When administered orally, it undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) isoenzymes into norketamine (through N-demethylation) and finally dehydronorketamine.[70] Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into 5-hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine.[71] As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent anesthetically, and plasma levels of this metabolite are three times higher than ketamine following oral administration.[67][72] Bioavailability through the oral route reaches 17–20%; bioavailability through other routes are: 93% intramuscularly, 25–50% intranasally, 30% sublingually, and 30% rectally.[40][70] Peak plasma concentrations are reached within a minute intravenously, 5–15 min intramuscularly, and 30 min orally.[72] Ketamine's duration of action in a clinical setting is 30 min to 2 h intramuscularly and 4–6 h orally.[40]

Plasma concentrations of ketamine are increased by diazepam and other CYP3A4 inhibitors.[40]

Chemistry

Structure

In chemical structure, ketamine is an arylcyclohexylamine derivative. Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in their enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.[73]

History

Medical use

Ketamine vials

Ketamine was first developed by Craig Newlands of Wayne State University and subsequently synthesized in 1962 by Calvin Stevens, a Parke Davis consultant conducting research on alpha-hydroxyimine rearrangements.[74][75] After promising preclinical research in animals, ketamine was introduced to testing in human prisoners in 1964.[75][76] These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over PCP as a dissociative anesthetic.[77] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.[78]

Nonmedical use

Nonmedical use of ketamine began on the West Coast of the United States in the early 1970s.[78] Early use was documented in underground literature such as The Fabulous Furry Freak Brothers. It was used in psychiatric and other academic research through the 1970s, culminating in 1978 with the publishing of psychonaut John Lilly's The Scientist, and Marcia Moore and Howard Alltounian's Journeys into the Bright World, which documented the unusual phenomenology of ketamine intoxication.[79] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.[80] However, its emergence as a club drug differs from other club drugs (e.g. MDMA) due to its anesthetic properties (e.g., slurred speech, immobilization) at higher doses;[81] in addition, there are reports of ketamine being sold as "ecstasy".[82] The use of ketamine as part of a "postclubbing experience" has also been documented.[83] Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.[81] Before becoming a federally controlled substance in the United States in 1999, ketamine was available as diverted pharmaceutical preparations and as a pure powder sold in bulk quantities from domestic chemical supply companies.[75] Much of the ketamine diverted for nonmedical use originates in China and India.[75]

Related to its ability to cause confusion and amnesiac effects, ketamine can leave users vulnerable to date rape.[31][78]

Society and culture

Ketamine is a "core" medicine in the World Health Organization's Essential Drugs List, a list of minimum medical needs for a basic healthcare system.[8]

Legal status

The increase in illicit use prompted ketamine's placement in Schedule III of the United States Controlled Substance Act in August 1999.[84]

In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[71][85] On 10 December 2013 the UK Advisory Council on the Misuse of Drugs (ACMD) recommended that the government reclassify ketamine to become a Class B drug,[86] and on 12 February 2014 the Home Office announced they would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage".[87][88]

The UK Minister of State for Crime Prevention, Norman Baker, responding to the ACMD's advice, said the issue of its recheduling for medical and veterinary would be addressed "separately to allow for a period of consultation."[87]

In Canada, ketamine is classified as a Schedule I narcotic, since 2005.[89] In Hong Kong, as of 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals, for university research purposes, or with a physician's prescription.[90][91] By 2002, ketamine was classified as class III in Taiwan; given the recent rise in prevalence in East Asia, however, rescheduling into class I or II is being considered.[71][92]

In December 2013, the government of India, in response to rising abuse and the use of ketamine as a date rape drug, has added it to Schedule X of the Drug and Cosmetics Act requiring a special license for sale and maintenance of records of all sales for two years.[93][94]

International brand names

Brand names for ketamine vary internationally:[37]

  • Anesject (ID)
  • Brevinaze (ZA)
  • Calypsol (AE, BB, BG, BH, BM, BS, BZ, CY, CZ, EG, GY, HU, IL, IQ, IR, JM, JO, KW, LB, LY, OM, PK, PL, PR, QA, RU, SA, SR, SY, TH, TT, YE)
  • Ivanes (ID)
  • Kanox (MY)
  • Keiran (VE)
  • Ketacor (PH)
  • Ketalar (AE, AR, AT, AU, BB, BE, BH, BM, BR, BS, BZ, CH, CY, DK, EG, ES, FI, FR, GB, GR, GY, HK, HN, ID, IE, IL, IN, IQ, IR, IT, JM, JO, KW, LB, LU, LY, MY, NL, NO, OM, PE, PT, QA, SA, SE, SR, SY, TR, TT, TW, US, UY, YE, ZA)
  • Ketalin (MX)
  • Ketamax (PH)
  • Ketamin-S (+) (PY)
  • Ketanest (NL, HR, PL, DE, AT)
  • Ketashort (CO)
  • Ketava (MY)
  • Ketazol (PH)
  • Ketmin (IN)
  • Ketalor (ES)
  • Narkamon (DE, PL)
  • Paard (BE)
  • Soon-Soon (TW)
  • Tekam (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE)
  • Velonarcon (PL)

Research

Treatment of addiction

Russian doctor Evgeny Krupitsky has claimed to have encouraging results by using ketamine as part of a treatment for alcohol addiction which combines psychedelic and aversive techniques.[95][96] Krupitsky and Kolp summarized their work to date in 2007.[97]

Veterinary medicine

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. It is an important part of the "rodent cocktail", a mixture of drugs used for anesthetizing rodents. Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help prevent pain wind-up. Ketamine is used to manage pain among large animals, though it has less effect on bovines. It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.

See also

References

    1. ↑ Hijazi, Y; Boulieu, R (July 2002). "Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes". Drug Metabolism and Disposition 30 (7): 853–8. doi:10.1124/dmd.30.7.853. PMID 12065445.
    2. ↑ 2.0 2.1 2.2 2.3 Green, SM; Roback, MG; Kennedy, RM; Krauss, B (2011). "Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update". Annals of Emergency Medicine 57 (5): 449–61. doi:10.1016/j.annemergmed.2010.11.030. PMID 21256625.
    3. ↑ 3.0 3.1 3.2 3.3 "Ketamine Injection Prescribing Information as of February 2013.". drugs.com. Retrieved 1 December 2014.
    4. ↑ 4.0 4.1 "Ketamine Side Effects". drugs.com. Retrieved 1 December 2014.
    5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12 5.13 5.14 5.15 Kohrs, R; Durieux, ME (November 1998). "Ketamine: Teaching an old drug new tricks". Anesthesia & Analgesia 87 (5): 1186–93. doi:10.1213/00000539-199811000-00039. PMID 9806706.
    6. ↑ Bergman, SA (1999). "Ketamine: Review of its pharmacology and its use in pediatric anesthesia". Anesthesia Progress 46 (1): 10–20. PMC 2148883. PMID 10551055.
    7. ↑ "Ketamine - CESAR". Center for substance abuse research. University of Maryland. Retrieved 26 September 2014.
    8. ↑ 8.0 8.1 WHO Model List of Essential Medicines (PDF) (18th ed.). World Health Organization. October 2013 [April 2013]. p. 1 [p. 5 of pdf]. Retrieved 22 April 2014.
    9. ↑ 9.0 9.1 Jansen, Karl (2001). Ketamine: Dreams and Realities. Multidisciplinary Association for Psychedelic Studies. pp. 50, 89. ISBN 0966001931.
    10. ↑ Heshmati, F; Zeinali, MB; Noroozinia, H; Abbacivash, R et al. (December 2003). "Use of ketamine in severe status asthmaticus in intensive care unit". Iranian Journal of Allergy, Asthma, and Immunology 2 (4): 175–80. PMID 17301376.
    11. ↑ Cohen, L; Athaide, V; Wickham, ME; Doyle-Waters, MM; Rose, NG; Hohl, CM (Jul 16, 2014). "The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review.". Annals of Emergency Medicine 65: 43–51.e2. doi:10.1016/j.annemergmed.2014.06.018. PMID 25064742.
    12. ↑ Nickson, Chris (7 August 2013). "Intubation, Hypotension and Shock". Life in the Fastlane (blog). Critical Care Compendium. Retrieved 10 April 2014.
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    14. ↑ Hemmingsen, C; Nielsen, JE (1991). "Intravenous ketamine for prevention of severe hypotension during spinal anaesthesia". Acta Anaesthesiologica Scandinavica 35 (8): 755–7. doi:10.1111/j.1399-6576.1991.tb03385.x. PMID 1763596.
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    16. ↑ Adams, HA (December 1997). "S-(+)-ketamin kreislaufinteraktionen bei totaler intravenöser anästhesie und analgosedierung" [S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation]. Der Anaesthesist (in German) 46 (12): 1081–7. doi:10.1007/s001010050510. PMID 9451493.
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    26. ↑ Tondo, L; Vázquez, GH; Baldessarini, RJ (February 2014). "Options for pharmacological treatment of refractory bipolar depression.". Current psychiatry reports 16 (2): 431. doi:10.1007/s11920-013-0431-y. PMID 24425269.
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    28. ↑ ECRI Institute, under contract to AHRQ. December 2013 AHRQ Healthcare Horizon Scanning System – Potential High-Impact Interventions Report. Priority Area 05: Depression and Other Mental Health Disorders
    29. ↑ National Institute of Mental Health (7 August 2006). "Experimental Medication Kicks Depression in Hours Instead of Weeks". NIH News (Press release). National Institutes of Health; Dept. of Health and Human Services; United States. National Institute of Mental Health director Thomas Insel said, "To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients."
    30. ↑ Naughton, M; Clarke, G; O'Leary, OF; Cryan, JF; Dinan, TG (Mar 2014). "A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action.". Journal of Affective Disorders 156: 24–35. doi:10.1016/j.jad.2013.11.014. PMID 24388038.
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