Abstract
Background
The acute and delayed effect of analgesic-range doses of ketamine on neurocognitive and behavioural outcomes is understudied. Using a non-controlled open-labelled design, three (1-h duration) increasing intravenous (IV) ketamine infusions comprising (i) 30 mg bolus of ketamine + 8 mg/h IV infusion, (ii) 12 mg/h IV infusion and (iii) 20 mg/h infusion were administered to 20 participants (15 male, 5 female, mean age = 30.8 years). Whole-blood ketamine and norketamine concentrations were determined at each treatment step and post-infusion.
Methods
The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to assess reaction/movement time (RTI, Simple and 5-Choice), visuospatial working memory (SWM), spatial planning (SOC) and subjective effects (visual analogue scale; VAS) during treatment and at post-treatment.
Results
Significant main effects were reported for time (dose) on CANTAB RTI 5-Choice reaction (F(4,18) = 3.41, p = 0.029) and movement time (F(4,18) = 4.42, p = 0.011), SWM (F(4,18) = 4.19, p = 0.014) and SOC (F(4,18) = 4.13, p = 0.015), but not RTI Simple reaction or movement time. Post hoc analyses revealed dose-dependent effects for both RTI 5-Choice reaction and movement time (all p < 0.05). Post-treatment performance on all neurocognitive and behavioural tasks returned to baseline levels. Regression analyses revealed a weak positive linear association between SWM ‘strategy’ score (R2 = 0.103, p < 0.001), all performance-based CANTAB VAS items (R2 range 0.005–0.137, all p < 0.05) and ketamine blood concentrations.
Discussion
The open-label, non-controlled trial design somewhat precludes the ability to adequately account for random treatment effects. Notwithstanding, these results suggest that analgesic doses of ketamine produce acute, selective, dose-dependent deficits in higher-order neurocognitive and behavioural domains.
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References
Aberl F, VanDine R (2005) Saliva and sweat testing with Drugwipe®. In: Wong RC, Tse HY (eds) Drugs of abuse: body fluid testing. Humana Press, Totowa, pp 161–175. https://doi.org/10.1007/978-1-59259-951-6_10
Anis NA, Berry SC, Burton NR, Lodge D (1983) The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol 79(2):565–575. https://doi.org/10.1111/j.1476-5381.1983.tb11031.x
Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med 47(3):211–218. https://doi.org/10.1111/j.2044-8341.1974.tb02285.x
Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP (1998) Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology 88(1):82–88. https://doi.org/10.1097/00000542-199801000-00015
Bristow A, Orlikowski C (1989) Subcutaneous ketamine analgesia: postoperative analgesia using subcutaneous infusions of ketamine and morphine. Ann R Coll Surg Engl 71(1):64–66
Carter LP, Kleykamp BA, Griffiths RR, Mintzer MZ (2013) Cognitive effects of intramuscular ketamine and oral triazolam in healthy volunteers. Psychopharmacology 226(1):53–63. https://doi.org/10.1007/s00213-012-2883-x
Clements JA, Nimmo WS (1981) Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 53(1):27–30. https://doi.org/10.1093/bja/53.1.27
Crisp BR, Swerissen H, Duckett SJ (2000) Four approaches to capacity building in health: consequences for measurement and accountability. Health Promot Int 15(2):99–107. https://doi.org/10.1093/heapro/15.2.99
Ghoneim MM, Hinrichs JV, Mewaldt SP, Petersen RC (1985) Ketamine: behavioral effects of subanesthetic doses. J Clin Psychopharmacol 5(2):70–77. https://doi.org/10.1097/00004714-198504000-00003
Guillermain Y, Micallef J, Possamaï C, Blin O, Hasbroucq T (2001) N-methyl-d-aspartate receptors and information processing: human choice reaction time under a subanaesthetic dose of ketamine. Neurosci Lett 303(1):29–32. https://doi.org/10.1016/S0304-3940(01)01695-0
Harborne GC, Watson FL, Healy DT, Groves L (1996) The effects of sub-anaesthetic doses of ketamine on memory, cognitive performance and subjective experience in healthy volunteers. J Psychopharmacol 10(2):134–140. https://doi.org/10.1177/026988119601000208
Hirota K, Lambert DG (1996) Ketamine: its mechanism(s) of action and unusual clinical uses. Br J Anaesth 77(4):441–444. https://doi.org/10.1093/bja/77.4.441
Honey RAE et al. (2003) Subdissociative dose ketamine produces a deficit in manipulation but not maintenance of the contents of working memory. Neuropsychopharmacology 28: doi:https://doi.org/10.1038/sj.npp.1300272
Jouguelet-Lacoste J, La Colla L, Schilling D, Chelly JE (2015) The use of intravenous infusion or single dose of low-dose ketamine for postoperative analgesia: a review of the current literature. Pain Med 16(2):383–403. https://doi.org/10.1111/pme.12619
Jurado MB, Rosselli M (2007) The elusive nature of executive functions: a review of our current understanding. Neuropsychol Rev 17(3):213–233. https://doi.org/10.1007/s11065-007-9040-z
Krystal JH, Bennett A, Abi-Saab D, Belger A, Karper LP, D’Souza DC, Lipschitz D, Abi-Dargham A, Charney DS (2000) Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions. Biol Psychiatry 47(2):137–143. https://doi.org/10.1016/S0006-3223(99)00097-9
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive nmda antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51(3):199–214. https://doi.org/10.1001/archpsyc.1994.03950030035004
Kurdi MS, Theerth KA, Deva RS (2014) Ketamine: current applications in anesthesia, pain, and critical care. Anesth Essays Res 8(3):283–290. https://doi.org/10.4103/0259-1162.143110
Lofwall MR, Griffiths RR, Mintzer MZ (2006) Cognitive and subjective acute dose effects of intramuscular ketamine in healthy adults. Exp Clin Psychopharmacol 14(4):439–449. https://doi.org/10.1037/1064-1297.14.4.439
Lou M-F, Yu P-J, Huang G-S, Dai Y-T (2004) Predicting post-surgical cognitive disturbance in older Taiwanese patients. Int J Nurs Stud 41(1):29–41. https://doi.org/10.1016/S0020-7489(03)00112-3
Lowe C, Rabbitt P (1998) Test\re-test reliability of the CANTAB and ISPOCD neuropsychological batteries: theoretical and practical issues. Neuropsychologia 36(9):915–923. https://doi.org/10.1016/S0028-3932(98)00036-0
Malhotra AK, Pinals DA, Weingartner H, Sirocco K, David Missar C, Pickar D, Breier A (1996) NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology 14(5):301–307. https://doi.org/10.1016/0893-133X(95)00137-3
Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D, Breier A (1997) Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology 17(3):141–150. https://doi.org/10.1016/s0893-133x(97)00036-5
Micallef J, Guillermain Y, Tardieu S, Hasbroucq T, Possamaï C, Jouve E, Blin O (2002) Effects of subanesthetic doses of ketamine on sensorimotor information processing in healthy subjects. Clin Neuropharmacol 25:101–106
Micallef J, Gavaudan G, Burle B, Blin O, Hasbroucq T (2004) A study of a topiramate pre-treatment on the effects induced by a subanaesthetic dose of ketamine on human reaction time. Neurosci Lett 369(2):99–103. https://doi.org/10.1016/j.neulet.2004.06.082
Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17(8):2921–2927
Morgan CJA, Curran HV (2006) Acute and chronic effects of ketamine upon human memory: a review. Psychopharmacology 188(4):408–424. https://doi.org/10.1007/s00213-006-0572-3
Morgan CJA, Mofeez A, Brandner B, Bromley L, Curran HV (2003) Acute effects of ketamine on memory systems and psychotic symptoms in healthy volunteers. Neuropsychopharmacology 29(1):208–218. https://doi.org/10.1038/sj.npp.1300342
Mortero RF, Clark LD, Tolan MM, Metz RJ, Tsueda K, Sheppard RA (2001) The effects of small-dose ketamine on propofol sedation: respiration, postoperative mood, perception, cognition, and pain. Anesth Analg 92:1465–1469. https://doi.org/10.1097/00000539-200106000-00022
Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20(2):106–118. https://doi.org/10.1016/S0893-133X(98)00067-0
Olofsen E, NoppersI NM, Kharasch E, Aarts L, Sarton E, Dahan A (2012) Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers. Anesthesiology 117(2):353–364. https://doi.org/10.1097/ALN.0b013e31825b6c91
Petrenko AB, Yamakura T, Baba H, Shimoji K (2003) The role of N-methyl-d-aspartate (NMDA) receptors in pain: a review. Anesth Analg 97:1108–1116. https://doi.org/10.1213/01.ane.0000081061.12235.55
Rao TS, Kim HS, Lehmann J, Martin LL, Wood PL (1989) Differential effects of phencyclidine (PCP) and ketamine on mesocortical and mesostriatal dopamine release in vivo. Life Sci 45(12):1065–1072. https://doi.org/10.1016/0024-3205(89)90163-X
Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacol 163(3-4):362–380. https://doi.org/10.1007/s00213-002-1154-7
Rogers R, Wise RG, Painter DJ, Longe SE, Tracey I (2004) An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging. Anesthesiology 100(2):292–301. https://doi.org/10.1097/00000542-200402000-00018
Shallice T (1982) Specific impairments of planning. Philos Trans R Soc Lond Ser B Biol Sci 298(1089):199–209. https://doi.org/10.1098/rstb.1982.0082
Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R (1996) Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 29(01):23–26. https://doi.org/10.1055/s-2007-979537
White PF, Way WL, Trevor AJ (1982) Ketamine—its pharmacology and therapeutic uses. Anesthesiology 56(2):119–136. https://doi.org/10.1097/00000542-198202000-00007
Wieber J, Gugler R, Hengstmann JH, Dengler HJ (1975) Pharmacokinetics of ketamine in man. Anaesthesist 24(6):260–263
Wong JJ, O’Daly O, Mehta MA, Young AH, Stone JM (2016) Ketamine modulates subgenual cingulate connectivity with the memory-related neural circuit—a mechanism of relevance to resistant depression? PeerJ 4:e1710. https://doi.org/10.7717/peerj.1710
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The research was approved by Monash Health Human Research Ethics committee (approval number: HREC/16/MonH/240). All participants provided written informed consent prior to commencing any study procedures. This study was registered on the Australia and New Zealand Clinical Trials registry (www.anzctr.com.au); trial number ACTRN12616001485426.
Conflict of interest
Dr. Amie Hayley is supported by a National Health and Medical Council (NHMRC) Peter Doherty Biomedical Early Career Research Fellowship (APP1119960). A/Prof Downey is supported by an NHMRC R.D. Wright Biomedical Career Development Fellowship (CDF: 2017-2020). Dr. Green, Dr. Keane, Ms. Kostakis and Prof Shehabi declare no potential conflicts of interest.
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Hayley, A., Green, M., Downey, L. et al. Neurocognitive and behavioural performance of healthy volunteers receiving an increasing analgesic-range infusion of ketamine. Psychopharmacology 235, 1273–1282 (2018). https://doi.org/10.1007/s00213-018-4842-7
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DOI: https://doi.org/10.1007/s00213-018-4842-7