Neurocognitive and behavioural performance of healthy volunteers receiving an increasing analgesic-range infusion of ketamine
- 251 Downloads
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.
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.
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.
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.
KeywordsKetamine Neurocognitive Behavioural Intravenous Therapeutic
Compliance with ethical standards
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.
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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 Google Scholar
- 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
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar